Search tips
Search criteria 


Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Neurochem Res. Author manuscript; available in PMC 2012 July 1.
Published in final edited form as:
PMCID: PMC3094593

Role of Inositol 1,4,5-Trishosphate Receptors in Pathogenesis of Huntington's Disease and Spinocerebellar Ataxias


Huntington's disease (HD) and spinocerebellar ataxias (SCAs) are autosomal-dominant neurodegenerative disorders. HD is caused by polyglutamine (polyQ) expansion in the amino-terminal region of a protein huntingtin (Htt) and primarily affects medium spiny striatal neurons (MSN). Many SCAs are caused by polyQ-expansion in ataxin proteins and primarily affect cerebellar Purkinje cells. The reasons for neuronal dysfunction and death in HD and SCAs remain poorly understood and no cure is available for the patients. Our laboratory discovered that mutant huntingtin, ataxin-2 and ataxin-3 proteins specifically bind to the carboxy-terminal region of the type 1 inositol 1,4,5-trisphosphate receptor (IP3R1), an intracellular Ca2+ release channel. Moreover, we found that association of mutant huntingtin or ataxins with IP3R1 causes sensitization of IP3R1 to activation by IP3 in planar lipid bilayers and in neuronal cells. These results suggested that deranged neuronal Ca2+ signaling might play an important role in pathogenesis of HD, SCA2 and SCA3. In support of this idea, we demonstrated a connection between abnormal Ca2+ signaling and neuronal cell death in experiments with HD, SCA2 and SCA3 transgenic mouse models. Additional data in the literature indicate that abnormal neuronal Ca2+ signaling may also play an important role in pathogenesis of SCAl, SCA5, SCA6, SCA14 and SCA15/16. Based on these results I propose that IP3R and other Ca2+ signaling proteins should be considered as potential therapeutic targets for treatment of HD and SCAs.

Keywords: Calcium signaling, Huntingtin, Neurodegeneration, Polyglutamine expansion, Inositol 1,4,,5-trisphosphate, Ataxin-2, Ataxin-3, Spinocerebellar ataxias, Transgenic mice, NMDA receptor, Apoptosis, Mitochondria, Memantine

Huntington Disease (HD) and Spinocerebellar Ataxias (SCA)

Huntington disease (HD) is an autosomal-dominant neurodegenerative disorder with the age of onset between 35 and 50 years and inexorable progression to death 15–20 years after onset. The symptoms include motor abnormalities including chorea and psychiatric disturbance with gradual dementia [1]. Neuropathological analysis reveals selective and progressive neuronal loss in the striatum (caudate nucleus, putamen and globus pallidus) [1, 2]. GABAergic medium spiny striatal neurons (MSN) are the most sensitive to neuronal degeneration in HD [1, 2]. Positional cloning efforts demonstrated that at the molecular level the cause of HD is polyglutamine (polyQ) expansion in the amino-terminal of a 350 kDa evolutionary conserved cytosolic protein called huntingtin (Htt) [3]. Clinical signs of HD develop if the length of polyQ track in Htt exceeds a pathological threshold of 35Q. The CAG repeat length is inversely correlated with age of onset [4]. Htt is widely expressed in the brain and in non-neuronal tissues and not particularly enriched in the striatum [57]. Htt plays an essential function in development, as deletion of the Htt gene in mice is embryonic lethal [8, 9]. Analysis of Htt primary sequence suggests that Htt is likely to function as a signaling scaffold [10], but the precise function of Htt in cells is not known. In order to elucidate the pathogenesis of HD, a number of transgenic HD mouse models have been generated [11]. Early symptoms of HD appear to be related to corticostriatal network dysfunction [1214]. At the early stage HD symptoms in many patients can be controlled by dopamine modulators, such as tetrabenazine, but eventually neuronal loss becomes too severe for effective symptomatic treatments [12, 14].

Spinocerebellar ataxias (SCAs) constitute a heterogeneous group of autosomal-dominant genetic and neurodegenerative disorders. SCAs are generally characterized by cerebellar atrophy and a progressive uncoordination of movement known as ataxia [1517]. A total of 29 SCAs have been identified and named in the chronological order of their discovery from SCA1 to SCA30. SCA15 and SCA16 are allelic [18, 19]. Although all SCA patients present with the phenotypic overlap of cerebellar atrophy and ataxia, other brain regions are differentially affected in each SCA. Seventeen genes have been associated with these SCAs and it is not understood how mutations in those SCA-associated genes lead to the SCA pathogenesis [20]. A significant fraction of SCAs, but not all SCAs, is caused by polyglutamine (polyQ) expansion mutations. The pathogenesis of SCAs is not fully understood, however, several different pathogenic mechanisms have been studied in SCAs such as dysregulation of transcription and gene expression, alterations in calcium homeostasis and synaptic neurotransmission, mitochondrial stress and apoptosis (reviewed in [2124]). Currently, therapy for SCA patients is mainly supportive and directed at treating individual symptoms in each patient using methods such as deep brain stimulation and levodopa supplements [2325]. No disease modifying therapy exists for any of the SCAs. In order to develop a successful treatment of SCAs, it will be important that a valid therapeutic target and the pathogenic pathways are identified.

Here I discuss recently emerging results that support the concept that excessive activity of inositol (1,4,5)-trisphosphate receptors and abnormal Ca2+ signaling is playing a major role in pathogenesis of HD and SCAs.

Mutant Huntingtin Specifically Sensitizes IP3R1 to IP3

The inositol (1,4,5)-trisphosphate receptor (IP3R) is an intracellular calcium (Ca2+) release channel that plays an important role in neuronal Ca2+ signaling [26]. Three isoforms of IP3R have been identified [27]. The type 1 receptor (IP3R1) is the predominant neuronal isoform. Mice lacking IP3R1 display severe ataxic behavior [28], and mice with a spontaneous mutation in the IP3R1 gene experience convulsions and ataxia [29], suggesting a major role of IP3R1 in neuronal function. Our laboratory has been heavily involved in elucidating the interaction between mHtt and IP3R1, as well as other Ca2+-related mechanisms relevant to HD (for reviews see [14, 30, 31]). We first discovered that mHtt binds directly and specifically to the C-terminal region of the type 1 IP3 receptor (IP3R1) [32]. Recently, unbiased high-throughput screening assays confirmed mHtt binding to IP3R1 [33]. Interestingly the affinity of mHtt to IP3R1 increases when mHtt is associated with HAP1a [32]. Moreover, mHtt, but not normal Htt, augmented IP3R1 activity in planar lipid bilayers [32]. Similarly, application of subthreshold concentrations of DHPG, an mGluR1/5 agonist, sensitized Ca2+ release in YAC128 primary MSN cultures [32]. This is consistent with the fact that glutamate-induced apoptosis of MSNs from YAC128 mice is mediated by mGluR1/5 and NR2B receptors [34]. In fact, specific blockade of IP3R1 with 2-APB and Enoxaparin is neuroprotective in the same model [34]. In a follow-up study, we found disturbed Ca2+ signaling, enhanced glutamate-induced apoptosis, and augmented NR2B activity in cultured MSNs from YAC128 mice, which express full-length human Htt, but these effects were completely absent in shortstop mice that express an amino-terminal fragment of mHtt (exons 1 and 2) and does not show HD pathology [35]. In more recent experiments, it was demonstrated that viral delivery of a peptide that disrupts mHtt association with IP3R1 protected YAC128 MSNs in vitro and in vivo [36]. Augmented IP3R1 activity further implicates mGluR5 receptor signaling in HD pathology. Importantly, inhibitors of IP3R1 may impede intracellular Ca2+ overload early in the disease state and protect MSNs from glutamate-induce excitotoxicity. MSN are highly enriched for mGluR5, a member of the group I mGluRs [3741]. Stimulation of group I mGluR in MSN leads to the generation of IP3 and release of Ca2+. The alterations in ER enzymes that have been observed in HD postmortem brains [42] are consistent with malfunction of ER Ca2+ handling in HD MSN neurons. Interestingly, recent findings from Dr Mikoshiba's laboratory directly implicated ER stress in HD pathogenesis. It was discovered in these studies that InsP3R1 association of ER stress chaperone protein GRP78 is impaired in Huntington's disease R6/2 model mice, resulting in misregulation of InsP3R1 gating [43].

Mutant Huntingtin Activates NR2B-Containing NMDA Receptors

MSN abundantly express NR2B subtype of NMDA receptors [4446]. In contrast to NMDA receptors containing NR2A subtype, NR2B-containing NMDA receptors have significant permeability for Ca2+ and activation of these receptors may have a dramatic effect on intracellular Ca2+ signals in MSN. Importantly, studies from Lynn Raymond's and Michael Hayden's laboratories suggested that expression of mutant Httexp protein facilitates activity of NR2B subtype of NMDAR receptors in a heterologous HEK293 cells expression system [47]. Interestingly, the potentiating effect of Httexp was specific for the NR1/NR2B NMDAR subtype and not for the NR1/NR2A NMDAR subtype. Using the same HEK293 cells expression system it was also demonstrated that cells co-transfected with NMDAR and Htt-138Q plasmids were more sensitive to NMDA-induced apoptosis than the cells co-transfected with NMDAR and Htt-15Q or GFP (control) plasmids [48]. Similar to effects on NMDAR currents, potentiating effects of Htt-138Q on excitotoxic cell death were more pronounced in the presence of the NR1/NR2B NMDAR subunit combination than in the presence of the NR1/NR2A subunit combination [48]. These initial findings were corroborated in the YAC mouse, whereby facilitation of NMDA-evoked current amplitude in MSNs from YAC72 and YAC128 mice compared to WT was induced by the NR1/NR2B receptor [35, 49]. Similarly, cultured MSNs from YAC72 mice showed enhanced NMDA-mediated cell death relative to WTs. Furthermore, treatment with ifenprodil, an NR2B-type selective antagonist, blocked most NMDA-mediated cell death in both YAC72 and WT mice [49]. The neuroprotective effect of ifenprodil was later recapitulated in YAC128 MSN cultures [34]. Findings from dissociated MSNs from presymptomatic R6/2 mice have revealed that NR2A, and not NR1 or NR2B, mRNA levels are reduced, which is concomitant with larger NR2B-mediated NMDAR currents compared to WTs [50].

The studies that indicated NR2A-type NMDARs are targeted primarily to the synapse and NR2B-type receptors are preferentially expressed at extrasynaptic sites (outside the synapse) are intriguing [5153]. In fact, dual roles for synaptic and extrasynaptic NMDARs have been proposed (for details see [54, 55]). Whereas synaptic NMDARs activate pro-survival pathways (e.g., CREB phosphorylation, BDNF transcription, ERK activation, antioxidant mechanisms), extrasynaptic NMDARs activate cell death pathways (e.g., loss of mitochondrial membrane potential, inhibition of ERK and BDNF, dendritic blebbing) [5658]. A recent study by Milnerwood and colleagues has shown that, indeed, mHtt results in increased extrasynaptic NMDAR expression and currents [59] (also see [60]). Examination of extrasynaptic activation, by mimicking glutamate spillover into the synaptic cleft with either strong evoked excitatory postsynaptic currents (EPSCs) or paired-pulse stimuli, revealed increased EPSC charge and elevated NMDA peak current and charge in presymptomatic (1 month) YAC128 MSNs relative to YAC18 [59]. Accordingly, application of TBOA, a GLT1 transport inhibitor that enhances glutamate spillover to extrasynaptic receptors, resulted in slowing of NMDAR EPSC kinetics in WT and YAC18 mice, but the slowing was consistently more augmented in YAC72 and YAC128. Moreover, in the presence of TBOA, NMDA currents and peak charge were larger in YAC128 compared to WT and YAC18, while YAC72 exhibited intermediate values. Altered TBOA-induced NMDA currents in YAC128 mice were ameliorated upon application of ifenprodil, which blocks NR2B extrasynaptic signaling. Spontaneous NMDA activity was not altered by mHtt, further suggesting involvement of NR2B-type and not NR2A-type NMDARs in altered MSN function. Surprisingly, treatment with low dose memantine, which is thought to preferentially antagonize extrasynaptic over synaptic NMDARs, in 2–4 month YAC128 mice resulted in increased CREB activation and improved motor learning (number of falls when learning the rotarod) relative to WTs [59]. Direct in vivo evidence for NR2B-mediated excitotoxicity in HD comes from recent findings demonstrating exacerbated striatal neurodegeneration in double-mutant mice that express 150Q and overexpress NR2B subunits [61].

How does mHtt augment NR2B activity? Numerous studies have investigated mRNA and protein expression of NDMARs in human postmortem brain and in HD mouse models, yet no conclusive correlation exists between CAG repeat number and receptor expression levels, nor receptor sensitivity (for discussion see [62]). Some studies suggested that Httexp affects NMDAR function via PSD95-dependent mechanism [63, 64]. Indeed, treatment of YAC72 and YAC128 MSN cultures with the Tat-NR2B9C peptide (200 nM), which blocks binding of NR2B with PSD95 and reduces surface expression of NMDARs, resulted in a marked reduction in NMDA-induced apoptosis [65]. Knockdown of PSD95 with siRNA resulted in the same effect in YAC128 MSNs [65]. Another possibility is related to changes in NMDAR trafficking to the plasma membrane in the presence of Httexp mutation [66]. Future experiments will be needed to clarify exact molecular mechanisms responsible for increase in NMDAR activity in HD MSNs.

From above discussion is clear that hyperfunction of extrasynaptic NMDARs (NR2B) is a major problem in HD and these receptors warrant targeting. The NR2B-specific inhibitors (e.g., ifenprodil, memantine) are likely candidates. Indeed, low dose memantine is neuroprotective in vitro [67, 68] and in vivo [59, 67]. Memantine demonstrated some beneficial effects in small scale pilot evaluation in HD patients [69] and large phase IV clinical trial of memantine in HD patients is currently in progress. Furthermore, a continued search for compounds that positively regulate synaptic NMDARs (NR2A) and/or negatively regulate extrasynaptic NMDARs (NR2B) is warranted.

Deranged Ca2+ Signaling and Apoptosis of HD MSN

Several lines of evidence indicate that glutamate-mediated excitotoxicity plays a role in neurodegeneration of HD MSN. Striatal injection of kainic acid induced death of MSN and yielded one of the first animal models of HD [70, 71]. Importantly, effects of kainate required presence of corticostriatal neurons [72], suggesting that glutamate release is required for kainate-induced MSN cell death. More direct evidence for an involvement of NMDAR was obtained when HD-like lesions were observed following striatal injection of the NMDAR agonist quinolinic acid [7375]. Consistent with the excitotoxicity hypothesis, striatal neurons from YAC72 mouse were sensitized to neuronal death induced by quinolinic acid and NMDA [49]. Moreover, excitotoxic cell death of YAC72 MSN was blocked by ifenprodil [49], supporting a direct involvement of NR1/NR2B NMDAR subtypes in HD.

Based on the results described above (Sects. “Mutant Huntingtin Specifically Sensitizes IP3R1 to IP3” and “Mutant Huntingtin Activates NR2B-Containing NMDA Receptors”) we previously suggested that overactivation of IP3R1-mediated Ca2+ release and NR2B-mediated Ca2+ influx in HD MSN may lead to Ca2+ overload and apoptosis of these neurons [30, 31]. To test this “Ca2+ hypothesis of HD” my laboratory used TUNEL assay to compare glutamate-induced apoptosis of MSN cultured from wild type mice and mice expressing mutant human Htt-128Q gene (YAC128 mouse [76]). The mice expressing normal human Htt-18Q gene (YAC18 [77]) was used as a control in these experiments. At 14 DIV all 3 groups of MSN were challenged by an 8 h application of glutamate (from 0 to 250 μM) to mimic physiological stimulation. Following exposure to glutamate, MSN were fixed, permeabilized and scored for apoptotic cell death using TUNEL staining. We determined that in basal conditions (no glutamate added) approximately 10% of MSN in all 3 experimental groups were apoptotic (TUNEL-positive). Addition of 25 μM or 50 μM glutamate increased the number of apoptotic cells to 15–20% in all 3 experimental groups. Addition of 100 μM or 250 μM glutamate increased apoptotic death to 60–70% for YAC128 MSN, but only to 25–30% for wild type and YAC18 MSN. Thus we reasoned that exposure to glutamate concentrations in 100–250 μM range leads to selective apoptosis of YAC128 MSN [34].

This “in vitro HD” model enabled us to test a connection between abnormal Ca2+ signaling and apoptosis of HD MSN. We found that inhibition of mGluR1/5 receptors (by a mixture of MPEP and CPCCOEt) reduced the glutamate-induced apoptosis of YAC128 MSN to WT MSN levels. NMDAR-inhibitor (+) MK801 or NR2B-specific antagonist ifenprodil had similar neuroprotective effects. Consistent with direct involvement of IP3R1, preincubation of the MSN cultures with a membrane-permeable IP3R blocker 2-APB [78] protected YAC128 MSN from glutamate-induced apoptosis [34]. All these results supported an idea that glutamate-induced Ca2+ overload play a key role in induction of apoptotic cell death of HD MSN.

IP3R and Abnormal Ca2+ Signaling in SCA2 Neurons

SCA2 patients suffer from a progressive cerebellar syndrome with ataxia of gait and stance, ataxia of limb movements, and dysarthria [1517]. Similar to HD, the SCA2 is caused by an expansion and translation of unstable CAG repeats in the gene encoding ataxin-2 from the normal 22 to more than 31 extra glutamine repeats [7981] (Table 1). The pathogenesis of SCA2 is currently not understood. Similar to wild type ataxin-2, polyglutamine-expanded ataxin-2 protein is ubiquitously expressed in cells without severe aggregation and formation of inclusion bodies [82], but the cerebellar PCs in SCA2 patients are mostly affected with a loss of over 75% [16]. Genetic knockouts of ATXN2 orthologs in fly and worm resulted in embryonic lethality [83, 84]. Atxn2 knockout mice were viable but displayed a late-onset obesity phenotype [85]. Mice deficient in Atxn2 did not show Purkinje cell loss or marked changes in the Purkinje cell dendritic tree [85]. Non-essential role of Atxn2 in rodents is most likely related to the presence of orthologs and redundancy in its function [85]. Thus, the polyglutamine expansion in ataxin-2 likely does not cause a loss of function nor a dominant negative effect but a gain of toxic function [85]. The role of calcium signaling in the pathogenesis of SCA2 is supported by the genetic association between polymorphisms in the CACNA1A gene and the age of disease onset in patients diagnosed with SCA2. The CACNA1A gene encodes the pore-forming α1A subunit of CaV2.1, a P/Q-type voltage-gated calcium channel. Patients with a prematurely early age of onset of SCA2 tended to have a longer CAG-repeat length in the CACNA1A gene [86]. Longer CAG-repeat lengths in this gene have been genetically linked to SCA6.

Table 1
Features of Spinocerebellar ataxias linked with abnormal neuronal Ca2+ signaling

The role of aberrant neuronal calcium signaling in SCA2 pathogenesis was strengthened further by a finding in our laboratory that ATX2exp but not wild type ATX2 (ATX2wt) specifically binds IP3R1 [87]. This suggested that its association would result in either a sensitization or desensitization of IP3R1 to activation by inositol 1,4,5-triphosphate (IP3) during glutamate signaling in PCs. PCs express extremely high levels of intracellular IP3R1 [88, 89], which are present on endoplasmic reticulum (ER) membranes. ATX2exp and ATX2wt were found to localize and associate with ER membranes [90]. In a lipid bilayer reconstitution experiment, we examined the effect of ATX2exp expression on IP3R1 activation in single channel recordings of IP3R1 co-expressed with ATX2exp. We found the presence of ATX2exp substantially sensitized IP3R1 to activation by inositol 1,4,5 triphosphate (IP3) [87].

To test the importance of Ca2+ signaling in SCA2 pathogenesis we performed a series of experiments with SCA2 transgenic mouse model (SCA2-58Q, generated by [82]) expressing 58 glutamine repeats (ATX2exp) in the ataxin-2 gene under the control of the L7/Pcp2 PC-specific promoter. These mice exhibit behavioral deficits, loss of Purkinje cell dendritic arborization and Purkinje cell death, which is progressive and akin to SCA2 patient pathology [82]. Consistent with involvement of excitotoxic mechanism, we discovered that PC cells in SCA2 mouse undergo dark cell degeneration (DCD) mode of cell death [24]. We found that there was a significant increase in calcium release from ER stores via ITPR1 in calcium imaging experiments in primary PCs cultured from SCA2-58Q transgenic mice, which was not observed in PCs cultured from wild type littermates [87]. When ryanodine or dantrolene were added to block ryanodine receptors and ER calcium release in PC cultures, the effect of ATX2exp expression was immediately reversed as ER calcium release returned to wild type levels [87]. In a TUNEL assay of PC death, we found that the addition of dantrolene to block the excessive ER calcium release caused by ATX2exp expression attenuated exogenous glutamate-induced PC death [87]. Furthermore, long-term feeding of SCA2-58Q mice with a calcium stabilizer dantrolene alleviated the age-dependent motor coordination deficits in these mice quantified by rotarod and beam-walk behavioral assays [87]. Stereological counting of PCs showed a rescue of PC death in 12-month old SCA2-58Q mice fed with dantrolene [87]. The above lines of evidence supported the hypothesis that deranged calcium signaling plays a role in SCA2 pathogenesis [23, 24, 87] (Table 1).

IP3R and Abnormal Ca2+ Signaling in SCA3 Neurons

SCA3 is a multi systemic disorder characterized by degeneration of spinocerebellar tracts, dentate nucleus, pontine and other brainstem nuclei, substantia nigra and pallidum [91]. In contrast to most other SCA, the cerebellar cortex and the inferior olives are widely spared. MRIs show cerebellar atrophy, which is less pronounced than in SCA2 in combination with brainstem atrophy. Nuclear inclusions containing expanded ataxin-3 have been found in neurons of affected brain regions. The clinical picture of SCA3 is characterized by a wide range of clinical manifestations, the precise nature of which partly depends on repeat length. All SCA3 patients suffer from a progressive syndrome with ataxia of gait and stance, ataxia of limb movements, and dysarthria [92]. The cause of SCA3 is a polyQ expansion in the carboxy-terminal of ataxin-3 (Atxn3) protein [93] (Table 1). The ataxin-3 is a 43 kDa cytosolic protein of 316 amino acids which contains amino-terminal Josephin domain and 3 ubiquitin-interactions motifs (UIMs) [94, 95]. Consistent with the presence of Josephin domain Atxn3 functions as deubiquitinating enzyme (DUB) [96]. The polyQ-expansion has no effect on DUB activity of Atxn3 [96, 97], so it is not likely that neurodegeneration in SCA3 develops due to impaired normal function of Atxn3. Ataxin-3 has been shown to act as a potent transcriptional repressor, a function that is probably related to its DUB activity [98]. Knockout of the ATXN3 gene in mice increases protein ubiquitination but does not result in an obvious behavioural phenotype [99].

Abnormal neuronal Ca2+ signaling has also been implicated in SCA3 pathogenesis. It was discovered that inhibition of Ca2+-dependent protease calpain suppressed aggregation of polyglutamine-expanded Atxn3 in transfected cells [100]. Similar to mutant Htt and mutant Atxn2, mutant Atxn3 but not wild type Atxn3 binds to and activates IP3R1, an intracellular Ca2+ release channel [101]. Moreover, long-term feeding of SCA3-YAC-84Q transgenic mouse with Ca2+ stabilizer dantrolene alleviated age-dependent motor coordination deficits in this mice and prevented neuronal loss in SNc and PN [101]. These results provided strong experimental support to the “Ca2+ hypothesis of SCA3 pathogenesis” [23, 24, 101] (Table 1).

Abnormal Neuronal Ca2+ Signaling in Other SCAs

The Ca2+ hypothesis is not only relevant for SCA2 and SCA3 but can be expanded to other SCAs [23, 24, 30, 102]. Deranged calcium signaling likely plays a role in the pathogenesis of SCA1. Similar to SCA2, SCA1 is caused by the translation of polyglutamine expansions, in the gene encoding ataxin-1 from the normal 30 (ATXN1wt) to over 40 expanded CAG repeats (ATXN1exp) (Table 1). ATXN1exp is widely expressed and selectively toxic in Purkinje cells [103]. Though its aggregation is not required to cause SCA1 pathology, ATXN1exp has to translocate to PC nuclei to cause cell death and ataxia [104]. In the nucleus, ATXN1exp alters transcription by destabilizing the RORα and SP-1 transcription factors [105, 106]. Microarray analyses of transgenic mouse models have shown that SCA1 mice may have altered calcium signaling. Early in SCA1 pathogenesis, SCA1 mice express significantly reduced levels of the calcium buffers calbindin and parvalbumin, ITPR1, type 1 inositol phosphate 5-phosphatase, ER calcium transporter SERCA, glutamate transporter EAAT4, EAAT4-stabilizer β-spectrin III, T-type volage gated calcium channels and transient receptor potential type 3 (TRPC3) calcium channels [105, 107109]. Since ITPR1 and SERCA2 have contradictory roles on ER calcium storage, it is possible that ATXN1exp downregulates the expression of only one of the two. One mechanism may be that by blocking ER loading, SERCA2 causes higher cytoplasmic calcium levels and the PC counteracts this effect by downregulating ITPR1 expression, which decreases ER calcium release and reduce cytoplasmic calcium levels [110]. We suggest that decreased expression of glutamate transporters in SCA1 could result in excitotoxic glutamate signaling that is upstream of calcium signaling leading to cytosolic calcium overload. Similar hypothesis has been previously proposed to explain SCA1 phenotype [109]. Reduced expression of calcium buffers could also decrease the ability of PCs to handle high calcium levels in the cytoplasm. Furthermore, SCA1 mice crossed with calbindin-knockout mice presented with an accelerated SCA1 phenotype [108], which supports the role of calcium buffers in working to relieve SCA1 PCs from excitotoxic calcium levels and the role of deranged calcium homeostasis in the progression of SCA pathogenesis. We have also found that mutant ATXN1exp specifically interacts with ITPR1 (X. Chen and I. Bezprozvanny, unpublished observations). As we have seen in SCA2, this suggests that excessive calcium release from ER stores via ITPR1s may also contribute to pathogenesis of SCA1. Therefore it would be necessary to study SCA1 mouse models further for any other change in calcium signaling besides the already reported differences in gene expression of calcium signaling proteins [105, 107, 108].

SCA6 is caused by a polyglutamine expansion in the C-terminus of a P/Q-type calcium channel, CaV2.1 (Table 1). It has been reported that this mutation enhances P/Q-type Ca2+ channels activity [111]. However, recent analysis of SCA6 knock-in mouse model indicated that pathology may be related to aggregation of mutant CaV2.1 subunits and reduction in the density of dendritic P/Q-type Ca2+ currents [112]. Animals expressing polyQ expanded CaV2.1 subunit exhibit age-dependent motor deficits and lower expression of the CaV2.1 channels but no difference in calbindin staining of slices when compared to WT [112]. This further supports our hypothesis of ataxia preceding cell death as these animals are ataxic in the absence of significant cell death. Future functional studies will be needed to understand alterations in Ca2+ signaling in PC cells from SCA6 mice.

Abnormal neuronal calcium signaling is not restricted to polyQ-expansion ataxias [102]. In SCA5, mutant β-III spectrin (SPTBN2) is unable to stabilize the glutamate transporter, excitatory amino acid transporter (EAAT4) on the PC membrane (Table 1). This would allow extended glutamate activation in the parallel fiber-PC synapse and lead to excitotoxicity in SCA5 [113]. Recent genetic evidence indicated that SCA14 is caused by mutations in protein kinase Cγ (PKCγ). PKCγ is highly expressed in PCs [114] (Table 1). Eighteen of the 22 identified mutations in PKCγ decrease the ability of PKCγ to phosphorylate and inactivate TRPC3 channels, which allow sustained calcium influx into the cell and results in elevated cytosolic calcium levels [115]. These calcium elevations, if left uncontrolled, could become toxic and result in PC loss via excitotoxic cascades described above. The rest of the mutations suppress calcium influx likely by hyperphosphorylating and over-inactivating TRPC3 channels [115]. Suppression of calcium signaling has been shown to be a cause of apoptotic cell death [116]. Therefore, even though we have described excitotoxicity as one possible effect of SCA-associated gene mutations on calcium signaling and cell survival, suppression of calcium signaling could be as detrimental as increasing it.

Unlike most of the SCAs we have discussed above, SCA15 and SCA16 are a result not of excitotoxity but of suppressed cytosolic calcium signaling (Table 1). SCA15 is genetically linked to 5′ deletions, total deletions or missense mutation (P1059L) in the gene encoding ITPR1 and located in 3p26.1–p25.3 chromosomal region [18, 117]. Although initial studies of SCA16 family suggested linkage to chromosome 8q22.1–24.1 [118], additional studies of the same family showed linkage to chromosome 3pter-p26.2 [119]. Initially point mutation in the 3′ untranslated region of the contactin 4 gene (CNTN4) located in the same region was implicated [119, 120], but more recent analysis demonstrated that the real cause of SCA16 is haploinsufficiency of ITPR1 expression due to heterozygous deletion of exons 1 to 48 of the ITPR1 gene [19]. Thus, SCA15 and SCA16 are the same disorder (SCA15/16), due to haploinsufficiency of ITPR1 (Table 1). Although, SCA15/16 is not polyQ disorder, aberrant calcium signaling is likely to play a role in pathogenesis given the high expression of ITPR1 in PCs [88], and their importance for stimulating BDNF production for PC dendritic morphology [121], and cerebellar plasticity [122]. There are at least two possible physiological roles of these alterations on ITPR1 function and calcium homeostasis in PC. A gain of function of ITPR1 could occur if the mutation or deletion causes constitutive activity or increased sensitivity to activation of the mutated protein. A loss of function could also occur if the mutation or deletion suppresses ITPR1 activation and signaling. Affected patients of SCA15 and mice with spontaneous mutations in ITPR1 express less ITPR1 protein [117]. As we await studies on the functional roles of the reported ITPR1 mutation and deletions in the pathogenesis of SCA15/16, we can only speculate that suppressed activity of ITPR1 s in SCA15/16 may uncouple plasticity mechanisms in PCs. Indeed, ITPR1 knockout mice do not survive past postnatal day 20–23 and completely lack cerebellar LTD, although hippocampal LTD is unaffected and hippocampal LTP is partially intact [121124]. Thus, disruption of ITPR1 expression or function may result in cerebellar-specific phenotypes, as observed in SCA15/16 patients.

Ca2+ Blockers and Perspectives for Clinical Intervention in HD and SCA Patients

Despite the fact that huntingtin and ataxins have been cloned more than 15 years ago, there is still no cure for these disorders. The most obvious targets are mutant huntingtin and ataxin proteins themselves. Expression of mutant Htt and mutant ataxin-1 (Atxn1) was reduced by injection of RNAi-encoding viruses, resulting in beneficial effects in mouse models of HD and SCA1 [125, 126]. Similar RNAi knockdown approach could also be expanded to other polyglutamine expansion SCAs. Selective knockdown of mRNA encoding mutant Htt and mutant Atxn3 proteins was recently demonstrated using peptide nucleic acid (PNA) and locked nucleic acid (LNA) antisense oligomers targeting expanded CAG repeats [127]. These are very attractive approaches, but their utility at the moment is limited by the absence of RNAi or antisense brain delivery system that can be used in humans.

In addition to reducing expression of polyQ-expanded proteins at the mRNA level, another potential therapeutic strategy is based on developing agents that selectively bind to mutant forms of these proteins. A polyQ-containing protein can exist in multiple conformations, some of which are nontoxic and some of which are aggregation-prone and toxic [128]. One possibility to reduce the amount of toxic conformations of Atxn2 and Atxn3 proteins by increasing the levels of chaperons, which control protein folding. Although these approaches are being developed for polyQ-expansion disorders [129131], they have not produced clinical leads yet. Several small molecules were isolated in screens as inhibitors of polyQ aggregation. Some of these molecules were able to reduce polyQ aggregation and toxicity in cellular and animal models [132137]. A specific polyQ binding peptide (QBP1) was isolated in the phage library screen [138]. It has been reported that QBP1 peptide prevented toxic conformational transition within polyQ-expanded proteins [138] and exerted neuroprotective effects in cellular and animal models of polyQ toxicity [139141]. Despite excellent scientific rational, so far none of these candidates has successfully advanced into clinical trials due to problems related to finding an appropriate mode of delivery, poor pharmacokinetics and low efficacy in vivo. Recent solution of the crystal structure of Htt exon 1 containing polyQ region [142] opens perspective for rational design of novel polyQ-binding therapeutic agents.

Our laboratory demonstrated beneficial effects of Ca2+ stabilizer dantrolene in both SCA2 and SCA3 mouse models [87, 101]. Dantrolene also has a long history of human use for treatment of malignant hyperthermia and for neurological indications. In considering design of the clinical trial potential side effects of long term exposure to dantrolene must be taken into consideration. NMDAR inhibitor memantine and anti-glutamate agent riluzole were neuroprotective in experiments with primary MSN cultures from YAC128 HD mouse model, with memantine being more effective [68]. Memantine was also effective in 3-NP model of HD [143] and in YAC128 genetic HD model [67]. Memantine demonstrated some beneficial effects in small scale pilot evaluation in HD patients [69] and is currently being tested soon in phase IV HD clinical trial. Riluzole was tested in phase III HD clinical trial, but it was not successful [144]. In addition to NMDAR, voltage-gated Ca2+ channels constitute another potential target for SCA treatment. In recent studies L-type Ca2+ channel inhibitor isradipine significantly protected SNc neurons in animal models of Parkinson's disease [145]. Moreover, a recent retrospective epidemiological study has found that treatment of hypertension with Ca2+ channel antagonists significantly diminished the risk of developing PD [146]. It is possible that isradipine and other dihydropyridines (DHP) may also be useful for treatment of HD and SCA patients. More conservative potential strategy involves use of mitochondrial stabilizers and energizers, such as creatine, CoQ10, and MitoQ. In previous neurodegenerative trials these compounds resulted in modest benefit [147] and it is likely that similar result will be obtained for SCA patients as well. Controlled clinical evaluation of Ca2+ inhibitors in HD and SCA patients will provide an ultimate test to the proposed “Ca2+ hypothesis” of these disorders.


I would like to thank members of my laboratory for their hard work. I am a holder of Carla Cocke Francis Professorship in Alzheimer's Research and supported by the McKnight Neuroscience of Brain Disorders Award. Our work on HD, SCA2 and SCA3 was supported by CHDI, Hereditary Disease Foundation, the National Organization for Rare Disorders, National Ataxia Foundation, Ataxia MJD Research Project, and the National Institutes of Health grants R01NS38082 and R01NS056224.


Special Issue: In Honor of Dr. Mikoshiba.


1. Vonsattel JP, DiFiglia M. Huntington disease. J Neuropathol Exp Neurol. 1998;57:369–384. [PubMed]
2. Vonsattel JP, Myers RH, Stevens TJ, Ferrante RJ, Bird ED, Richardson EP., Jr Neuropathological classification of Huntington's disease. J Neuropathol Exp Neurol. 1985;44:559–577. [PubMed]
3. The Huntington's Disease Collaborative Research and Group A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell. 1993;72:971–983. [PubMed]
4. Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length. Clin Genet. 2004;65:267–277. [PubMed]
5. Li SH, Schilling G, Young WS, III, Li XJ, Margolis RL, Stine OC, Wagster MV, Abbott MH, Franz ML, Ranen NG, et al. Huntington's disease gene (IT15) is widely expressed in human and rat tissues. Neuron. 1993;11:985–993. [PubMed]
6. Strong TV, Tagle DA, Valdes JM, Elmer LW, Boehm K, Swaroop M, Kaatz KW, Collins FS, Albin RL. Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues. Nat Genet. 1993;5:259–265. [PubMed]
7. Sharp AH, Loev SJ, Schilling G, Li SH, Li XJ, Bao J, Wagster MV, Kotzuk JA, Steiner JP, Lo A, et al. Widespread expression of Huntington's disease gene (IT15) protein product. Neuron. 1995;14:1065–1074. [PubMed]
8. Nasir J, Floresco SB, O'Kusky JR, Diewert VM, Richman JM, Zeisler J, Borowski A, Marth JD, Phillips AG, Hayden MR. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995;81:811–823. [PubMed]
9. Duyao MP, Auerbach AB, Ryan A, Persichetti F, Barnes GT, McNeil SM, Ge P, Vonsattel JP, Gusella JF, Joyner AL, et al. Inactivation of the mouse Huntington's disease gene homolog Hdh. Science. 1995;269:407–410. [PubMed]
10. MacDonald ME. Huntingtin: alive and well and working in middle management. Sci STKE. 2003;2003:pe48. [PubMed]
11. Heng MY, Detloff PJ, Albin RL. Rodent genetic models of Huntington disease. Neurobiol Dis. 2008;32:1–9. [PubMed]
12. Andre VM, Cepeda C, Levine MS. Dopamine and glutamate in Huntington's disease: a balancing act. CNS Neurosci Ther. 2010;16:163–178. [PMC free article] [PubMed]
13. Milnerwood AJ, Raymond LA. Early synaptic pathophysiology in neurodegeneration: insights from Huntington's disease. Trends Neurosci. 2010;33:513–523. [PubMed]
14. Miller BR, Bezprozvanny I. Corticostriatal circuit dysfunction in Huntington's disease: intersection of glutamate, dopamine, and calcium. Future Neurol. 2010;5:735–756. [PMC free article] [PubMed]
15. Filla A, De Michele G, Santoro L, Calabrese O, Castaldo I, Giuffrida S, Restivo D, Serlenga L, Condorelli DF, Bonuccelli U, Scala R, Coppola G, Caruso G, Cocozza S. Spinocerebellar ataxia type 2 in southern Italy: a clinical and molecular study of 30 families. J Neurol. 1999;246:467–471. [PubMed]
16. Schols L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3:291–304. [PubMed]
17. Lastres-Becker I, Rub U, Auburger G. Spinocerebellar ataxia 2 (SCA2) Cerebellum. 2008;7:115–124. [PubMed]
18. Hara K, Shiga A, Nozaki H, Mitsui J, Takahashi Y, Ishiguro H, Yomono H, Kurisaki H, Goto J, Ikeuchi T, Tsuji S, Nishizawa M, Onodera O. Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. Neurology. 2008;71:547–551. [PubMed]
19. Iwaki A, Kawano Y, Miura S, Shibata H, Matsuse D, Li W, Furuya H, Ohyagi Y, Taniwaki T, Kira J, Fukumaki Y. Heterozygous deletion of ITPR1, but not SUMF1, in spinocerebellar ataxia type 16. J Med Genet. 2008;45:32–35. [PubMed]
20. Paulson HL. The spinocerebellar ataxias. J Neuroophthalmol. 2009;29:227–237. [PMC free article] [PubMed]
21. Matilla-Duenas A, Sanchez I, Corral-Juan M, Davalos A, Alvarez R, Latorre P. Cellular and molecular pathways triggering neurodegeneration in the spinocerebellar ataxias. Cerebellum. 2010;9:148–166. [PubMed]
22. Carlson KM, Andresen JM, Orr HT. Emerging pathogenic pathways in the spinocerebellar ataxias. Curr Opin Genet Dev. 2009;19:247–253. [PMC free article] [PubMed]
23. Bezprozvanny I, Klockgether T. Therapeutic prospects for spinocerebellar ataxia type 2 and 3. Drugs Future. 2010;34:991–999. [PMC free article] [PubMed]
24. Kasumu A, Bezprozvanny I. Deranged calcium signaling in purkinje cells and pathogenesis in spinocerebellar ataxia 2 (SCA2) and other ataxias. Cerebellum. 2010 Epub ahead of print. [PMC free article] [PubMed]
25. Pirker W, Back C, Gerschlager W, Laccone F, Alesch F. Chronic thalamic stimulation in a patient with spinocerebellar ataxia type 2. Mov Disord. 2003;18:222–225. [PubMed]
26. Berridge MJ. Neuronal calcium signaling. Neuron. 1998;21:13–26. [PubMed]
27. Furuichi T, Kohda K, Miyawaki A, Mikoshiba K. Intracellular channels. Curr Opinion Neurobiol. 1994;4:294–303. [PubMed]
28. Matsumoto M, Nakagawa T, Inoue T, Nagata E, Tanaka K, Takano H, Minowa O, Kuno J, Sakakibara S, Yamada M, Yoneshima H, Miyawaki A, Fukuuchi Y, Furuichi T, Okano H, Mikoshiba K, Noda T. Ataxia and epileptic seizures in mice lacking type 1 inositol 1,4,5-trisphosphate receptor. Nature. 1996;379:168–171. [PubMed]
29. Street VA, Bosma MM, Demas VP, Regan MR, Lin DD, Robinson LC, Agnew WS, Tempel BL. The type 1 inositol 1, 4, 5-trisphosphate receptor gene is altered in the opisthotonos mouse. J Neurosci. 1997;17:635–645. [PubMed]
30. Bezprozvanny I. Calcium signaling and neurodegenerative diseases. Trends Mol Med. 2009;15:89–100. [PMC free article] [PubMed]
31. Bezprozvanny I, Hayden MR. Deranged neuronal calcium signaling and Huntington disease. Biochem Biophys Res Commun. 2004;322:1310–1317. [PubMed]
32. Tang TS, Tu H, Chan EY, Maximov A, Wang Z, Wellington CL, Hayden MR, Bezprozvanny I. Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1. Neuron. 2003;39:227–239. [PMC free article] [PubMed]
33. Kaltenbach LS, Romero E, Becklin RR, Chettier R, Bell R, Phansalkar A, Strand A, Torcassi C, Savage J, Hurlburt A, Cha GH, Ukani L, Chepanoske CL, Zhen Y, Sahasrabudhe S, Olson J, Kurschner C, Ellerby LM, Peltier JM, Botas J, Hughes RE. Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet. 2007;3:e82. [PubMed]
34. Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinas R, Kristal BS, Hayden MR, Bezprozvanny I. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease. Proc Natl Acad Sci USA. 2005;102:2602–2607. [PubMed]
35. Zhang H, Li Q, Graham RK, Slow E, Hayden MR, Bezprozvanny I. Full length mutant huntingtin is required for altered Ca2+ signaling and apoptosis of striatal neurons in the YAC mouse model of Huntington's disease. Neurobiol Dis. 2008;31:80–88. [PMC free article] [PubMed]
36. Tang TS, Guo C, Wang H, Chen X, Bezprozvanny I. Neuroprotective effects of inositol 1,4,5-trisphosphate receptor C-terminal fragment in a Huntington's disease mouse model. J Neurosci. 2009;29:1257–1266. [PMC free article] [PubMed]
37. Mao L, Wang JQ. Upregulation of preprodynorphin and preproenkephalin mRNA expression by selective activation of group I metabotropic glutamate receptors in characterized primary cultures of rat striatal neurons. Brain Res Mol Brain Res. 2001;86:125–137. [PubMed]
38. Mao L, Wang JQ. Glutamate cascade to cAMP response element-binding protein phosphorylation in cultured striatal neurons through calcium-coupled group I metabotropic glutamate receptors. Mol Pharmacol. 2002;62:473–484. [PubMed]
39. Tallaksen-Greene SJ, Kaatz KW, Romano C, Albin RL. Localization of mGluR1a-like immunoreactivity and mGluR5-like immunoreactivity in identified populations of striatal neurons. Brain Res. 1998;780:210–217. [PubMed]
40. Kerner JA, Standaert DG, Penney JB, Jr, Young AB, Landwehrmeyer GB. Expression of group one metabotropic glutamate receptor subunit mRNAs in neurochemically identified neurons in the rat neostriatum, neocortex, and hippocampus. Brain Res Mol Brain Res. 1997;48:259–269. [PubMed]
41. Testa CM, Standaert DG, Landwehrmeyer GB, Penney JB, Jr, Young AB. Differential expression of mGluR5 metabotropic glutamate receptor mRNA by rat striatal neurons. J Comp Neurol. 1995;354:241–252. [PubMed]
42. Cross AJ, Crow TJ, Johnson JA, Dawson JM, Peters TJ. Loss of endoplasmic reticulum-associated enzymes in affected brain regions in Huntington's disease and Alzheimer-type dementia. J Neurol Sci. 1985;71:137–143. [PubMed]
43. Higo T, Hamada K, Hisatsune C, Nukina N, Hashikawa T, Hattori M, Nakamura T, Mikoshiba K. Mechanism of ER stress-induced brain damage by IP3 receptor. Neuron. 2010;68(5):865–878. [PubMed]
44. Landwehrmeyer GB, Standaert DG, Testa CM, Penney JB, Jr, Young AB. NMDA receptor subunit mRNA expression by projection neurons and interneurons in rat striatum. J Neurosci. 1995;15:5297–5307. [PubMed]
45. Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12:529–540. [PubMed]
46. Portera-Cailliau C, Price DL, Martin LJ. N-methyl-D-aspartate receptor proteins NR2A and NR2B are differentially distributed in the developing rat central nervous system as revealed by subunit-specific antibodies. J Neurochem. 1996;66:692–700. [PubMed]
47. Chen N, Luo T, Wellington C, Metzler M, McCutcheon K, Hayden MR, Raymond LA. Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin. J Neurochem. 1999;72:1890–1898. [PubMed]
48. Zeron MM, Chen N, Moshaver A, Lee AT, Wellington CL, Hayden MR, Raymond LA. Mutant huntingtin enhances excitotoxic cell death. Mol Cell Neurosci. 2001;17:41–53. [PubMed]
49. Zeron MM, Hansson O, Chen N, Wellington CL, Leavitt BR, Brundin P, Hayden MR, Raymond LA. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron. 2002;33:849–860. [PubMed]
50. Ali NJ, Levine MS. Changes in expression of N-methyl-D-aspartate receptor subunits occur early in the R6/2 mouse model of Huntington's disease. Dev Neurosci. 2006;28:230–238. [PubMed]
51. Li JH, Wang YH, Wolfe BB, Krueger KE, Corsi L, Stocca G, Vicini S. Developmental changes in localization of NMDA receptor subunits in primary cultures of cortical neurons. Eur J Neurosci. 1998;10:1704–1715. [PubMed]
52. Stocca G, Vicini S. Increased contribution of NR2A subunit to synaptic NMDA receptors in developing rat cortical neurons. J Physiol. 1998;507(Pt 1):13–24. [PubMed]
53. Tovar KR, Westbrook GL. The incorporation of NMDA receptors with a distinct subunit composition at nascent hippocampal synapses in vitro. J Neurosci. 1999;19:4180–4188. [PubMed]
54. Papadia S, Hardingham GE. The dichotomy of NMDA receptor signaling. Neuroscientist. 2007;13:572–579. [PMC free article] [PubMed]
55. Vanhoutte P, Bading H. Opposing roles of synaptic and extrasynaptic NMDA receptors in neuronal calcium signalling and BDNF gene regulation. Curr Opin Neurobiol. 2003;13:366–371. [PubMed]
56. Gouix E, Leveille F, Nicole O, Melon C, Had-Aissouni L, Buisson A. Reverse glial glutamate uptake triggers neuronal cell death through extrasynaptic NMDA receptor activation. Mol Cell Neurosci. 2009;40:463–473. [PubMed]
57. Hardingham GE, Fukunaga Y, Bading H. Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways. Nat Neurosci. 2002;5:405–414. [PubMed]
58. Papadia S, Soriano FX, Leveille F, Martel MA, Dakin KA, Hansen HH, Kaindl A, Sifringer M, Fowler J, Stefovska V, McKenzie G, Craigon M, Corriveau R, Ghazal P, Horsburgh K, Yankner BA, Wyllie DJ, Ikonomidou C, Hardingham GE. Synaptic NMDA receptor activity boosts intrinsic antioxidant defenses. Nat Neurosci. 2008;11:476–487. [PMC free article] [PubMed]
59. Milnerwood AJ, Gladding CM, Pouladi MA, Kaufman AM, Hines RM, Boyd JD, Ko RW, Vasuta OC, Graham RK, Hayden MR, Murphy TH, Raymond LA. Early increase in extrasynaptic NMDA receptor signaling and expression contributes to phenotype onset in Huntington's disease mice. Neuron. 2010;65:178–190. [PubMed]
60. Li L, Murphy TH, Hayden MR, Raymond LA. Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease. J Neurophysiol. 2004;92:2738–2746. [PubMed]
61. Heng MY, Detloff PJ, Wang PL, Tsien JZ, Albin RL. In vivo evidence for NMDA receptor-mediated excitotoxicity in a murine genetic model of Huntington disease. J Neurosci. 2009;29:3200–3205. [PubMed]
62. Milnerwood AJ, Raymond LA. Synaptic abnormalities associated with Huntington's disease. In: Dityatev AE-HaA., editor. molecular mechanisms of synaotogenesis. Springer; New York: 2006. pp. 457–469.
63. Sun Y, Savanenin A, Reddy PH, Liu YF. Polyglutamine-expanded huntingtin promotes sensitization of N-methyl-D-aspartate receptors via post-synaptic density 95. J Biol Chem. 2001;276:24713–24718. [PubMed]
64. Song C, Zhang Y, Parsons CG, Liu YF. Expression of polyglutamine-expanded huntingtin induces tyrosine phosphorylation of N-methyl-D-aspartate receptors. J Biol Chem. 2003;278:33364–33369. [PubMed]
65. Fan J, Cowan CM, Zhang LY, Hayden MR, Raymond LA. Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington's disease. J Neurosci. 2009;29:10928–10938. [PubMed]
66. Fan MM, Fernandes HB, Zhang LY, Hayden MR, Raymond LA. Altered NMDA receptor trafficking in a yeast artificial chromosome transgenic mouse model of Huntington's disease. J Neurosci. 2007;27:3768–3779. [PubMed]
67. Okamoto S, Pouladi MA, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Vincent Chen HS, Tong G, Hayden MR, Lipton SA. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med. 2009;15:1407–1413. [PMC free article] [PubMed]
68. Wu J, Tang T, Bezprozvanny I. Evaluation of clinically relevant glutamate pathway inhibitors in in vitro model of Huntington's disease. Neurosci Lett. 2006;407:219–223. [PubMed]
69. Ondo WG, Mejia NI, Hunter CB. A pilot study of the clinical efficacy and safety of memantine for Huntington's disease. Parkinsonism Relat Disord. 2007;13:453–454. [PubMed]
70. Coyle JT, Schwarcz R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature. 1976;263:244–246. [PubMed]
71. McGeer EG, McGeer PL. Duplication of biochemical changes of Huntington's chorea by intrastriatal injections of glutamic and kainic acids. Nature. 1976;263:517–519. [PubMed]
72. McGeer EG, McGeer PL, Singh K. Kainate-induced degeneration of neostriatal neurons: dependency upon corticostriatal tract. Brain Res. 1978;139:381–383. [PubMed]
73. Beal MF, Kowall NW, Ellison DW, Mazurek MF, Swartz KJ, Martin JB. Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature. 1986;321:168–171. [PubMed]
74. Hantraye P, Riche D, Maziere M, Isacson O. A primate model of Huntington's disease: behavioral and anatomical studies of unilateral excitotoxic lesions of the caudate-putamen in the baboon. Exp Neurol. 1990;108:91–104. [PubMed]
75. Beal MF, Ferrante RJ, Swartz KJ, Kowall NW. Chronic quinolinic acid lesions in rats closely resemble Huntington's disease. J Neurosci. 1991;11:1649–1659. [PubMed]
76. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, Deng Y, Oh R, Bissada N, Hossain SM, Yang YZ, Li XJ, Simpson EM, Gutekunst CA, Leavitt BR, Hayden MR. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet. 2003;12:1555–1567. [PubMed]
77. Hodgson JG, Agopyan N, Gutekunst CA, Leavitt BR, LePiane F, Singaraja R, Smith DJ, Bissada N, McCutcheon K, Nasir J, Jamot L, Li XJ, Stevens ME, Rosemond E, Roder JC, Phillips AG, Rubin EM, Hersch SM, Hayden MR. A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron. 1999;23:181–192. [PubMed]
78. Maruyama T, Kanaji T, Nakade S, Kanno T, Mikoshiba K. 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. J Biochem (Tokyo) 1997;122:498–505. [PubMed]
79. Pulst SM, Nechiporuk A, Nechiporuk T, Gispert S, Chen XN, Lopes-Cendes I, Pearlman S, Starkman S, Orozco-Diaz G, Lunkes A, DeJong P, Rouleau GA, Auburger G, Korenberg JR, Figueroa C, Sahba S. Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996;14:269–276. [PubMed]
80. Imbert G, Saudou F, Yvert G, Devys D, Trottier Y, Garnier JM, Weber C, Mandel JL, Cancel G, Abbas N, Durr A, Didierjean O, Stevanin G, Agid Y, Brice A. Cloning of the gene for spinocerebellar ataxia 2 reveals a locus with high sensitivity to expanded CAG/glutamine repeats. Nat Genet. 1996;14:285–291. [PubMed]
81. Sanpei K, Takano H, Igarashi S, Sato T, Oyake M, Sasaki H, Wakisaka A, Tashiro K, Ishida Y, Ikeuchi T, Koide R, Saito M, Sato A, Tanaka T, Hanyu S, Takiyama Y, Nishizawa M, Shimizu N, Nomura Y, Segawa M, Iwabuchi K, Eguchi I, Tanaka H, Takahashi H, Tsuji S. Identification of the spinocerebellar ataxia type 2 gene using a direct identification of repeat expansion and cloning technique, DIRECT. Nat Genet. 1996;14:277–284. [PubMed]
82. Huynh DP, Figueroa K, Hoang N, Pulst SM. Nuclear localization or inclusion body formation of ataxin-2 are not necessary for SCA2 pathogenesis in mouse or human. Nat Genet. 2000;26:44–50. [PubMed]
83. Kiehl TR, Shibata H, Pulst SM. The ortholog of human ataxin-2 is essential for early embryonic patterning in C. elegans. J Mol Neurosci. 2000;15:231–241. [PubMed]
84. Satterfield TF, Jackson SM, Pallanck LJ. A drosophila homolog of the polyglutamine disease gene SCA2 is a dosage-sensitive regulator of actin filament formation. Genetics. 2002;162:1687–1702. [PubMed]
85. Kiehl TR, Nechiporuk A, Figueroa KP, Keating MT, Huynh DP, Pulst SM. Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochem Biophys Res Commun. 2006;339:17–24. [PubMed]
86. Pulst SM, Santos N, Wang D, Yang H, Huynh D, Velazquez L, Figueroa KP. Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset. Brain. 2005;128:2297–2303. [PubMed]
87. Liu J, Tang TS, Tu H, Nelson O, Herndon E, Huynh DP, Pulst SM, Bezprozvanny I. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 2. J Neurosci. 2009;29:9148–9162. [PMC free article] [PubMed]
88. Furuichi T, Simon-Chazottes D, Fujino I, Yamada N, Hasegawa M, Miyawaki A, Yoshikawa S, Guenet JL, Mikoshiba K. Widespread expression of inositol 1, 4, 5-trisphosphate receptor type 1 gene (Insp3r1) in the mouse central nervous system. Recept Channels. 1993;1:11–24. [PubMed]
89. Sharp AH, Nucifora FC, Jr, Blondel O, Sheppard CA, Zhang C, Snyder SH, Russell JT, Ryugo DK, Ross CA. Differential cellular expression of isoforms of inositol 1,4,5-triphosphate receptors in neurons and glia in brain. J Comp Neurol. 1999;406:207–220. [PubMed]
90. van de Loo S, Eich F, Nonis D, Auburger G, Nowock J. Ataxin-2 associates with rough endoplasmic reticulum. Exp Neurol. 2009;215:110–118. [PubMed]
91. Stevanin G, Durr A, Brice A. Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology. Eur J Hum Genet. 2000;8:4–18. [PubMed]
92. Coutinho P, Andrade C. Autosomal dominant system degeneration in Portuguese families of the Azores Islands. A new genetic disorder involving cerebellar, pyramidal, extrapyramidal and spinal cord motor functions. Neurology. 1978;28:703–709. [PubMed]
93. Paulson HL, Das SS, Crino PB, Perez MK, Patel SC, Gotsdiner D, Fischbeck KH, Pittman RN. Machado-Joseph disease gene product is a cytoplasmic protein widely expressed in brain. Ann Neurol. 1997;41:453–462. [PubMed]
94. Scheel H, Tomiuk S, Hofmann K. Elucidation of ataxin-3 and ataxin-7 function by integrative bioinformatics. Hum Mol Genet. 2003;12:2845–2852. [PubMed]
95. Albrecht M, Golatta M, Wullner U, Lengauer T. Structural and functional analysis of ataxin-2 and ataxin-3. Eur J Biochem. 2004;271:3155–3170. [PubMed]
96. Burnett B, Li F, Pittman RN. The polyglutamine neurodegenerative protein ataxin-3 binds polyubiquitylated proteins and has ubiquitin protease activity. Hum Mol Genet. 2003;12:3195–3205. [PubMed]
97. Winborn BJ, Travis SM, Todi SV, Scaglione KM, Xu P, Williams AJ, Cohen RE, Peng J, Paulson HL. The deubiquitinating enzyme ataxin-3, a polyglutamine disease protein, edits Lys63 linkages in mixed linkage ubiquitin chains. J Biol Chem. 2008;283:26436–26443. [PMC free article] [PubMed]
98. Evert BO, Araujo J, Vieira-Saecker AM, de Vos RA, Harendza S, Klockgether T, Wullner U. Ataxin-3 represses transcription via chromatin binding, interaction with histone deacetylase 3, and histone deacetylation. J Neurosci. 2006;26:11474–11486. [PubMed]
99. Schmitt I, Linden M, Khazneh H, Evert BO, Breuer P, Klockgether T, Wuellner U. Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination. Biochem Biophys Res Commun. 2007;362:734–739. [PubMed]
100. Haacke A, Hartl FU, Breuer P. Calpain inhibition is sufficient to suppress aggregation of polyglutamine-expanded ataxin-3. J Biol Chem. 2007;282:18851–18856. [PubMed]
101. Chen X, Tang TS, Tu H, Nelson O, Pook M, Hammer R, Nukina N, Bezprozvanny I. Deranged calcium signaling and neurodegeneration in spinocerebellar ataxia type 3. J Neurosci. 2008;28:12713–12724. [PMC free article] [PubMed]
102. Schorge S, van de Leemput J, Singleton A, Houlden H, Hardy J. Human ataxias: a genetic dissection of inositol triphosphate receptor (ITPR1)-dependent signaling. Trends Neurosci. 2010;33:211–219. [PMC free article] [PubMed]
103. Zoghbi HY, Orr HT. Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1. J Biol Chem. 2009;284:7425–7429. [PMC free article] [PubMed]
104. Klement IA, Skinner PJ, Kaytor MD, Yi H, Hersch SM, Clark HB, Zoghbi HY, Orr HT. Ataxin-1 nuclear localization and aggregation: role in polyglutamine-induced disease in SCA1 transgenic mice. Cell. 1998;95:41–53. [PubMed]
105. Serra HG, Duvick L, Zu T, Carlson K, Stevens S, Jorgensen N, Lysholm A, Burright E, Zoghbi HY, Clark HB, Andresen JM, Orr HT. RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice. Cell. 2006;127:697–708. [PubMed]
106. Goold R, Hubank M, Hunt A, Holton J, Menon RP, Revesz T, Pandolfo M, Matilla-Duenas A. Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1. Hum Mol Genet. 2007;16:2122–2134. [PubMed]
107. Lin X, Antalffy B, Kang D, Orr HT, Zoghbi HY. Polyglutamine expansion down-regulates specific neuronal genes before pathologic changes in SCA1. Nat Neurosci. 2000;3:157–163. [PubMed]
108. Vig PJ, Subramony SH, Qin Z, McDaniel DO, Fratkin JD. Relationship between ataxin-1 nuclear inclusions and Purkinje cell specific proteins in SCA-1 transgenic mice. J Neurol Sci. 2000;174:100–110. [PubMed]
109. Serra HG, Byam CE, Lande JD, Tousey SK, Zoghbi HY, Orr HT. Gene profiling links SCA1 pathophysiology to glutamate signaling in Purkinje cells of transgenic mice. Hum Mol Genet. 2004;13:2535–2543. [PubMed]
110. Inoue T, Lin X, Kohlmeier KA, Orr HT, Zoghbi HY, Ross WN. Calcium dynamics and electrophysiological properties of cerebellar Purkinje cells in SCA1 transgenic mice. J Neurophysiol. 2001;85:1750–1760. [PubMed]
111. Piedras-Renteria ES, Watase K, Harata N, Zhuchenko O, Zoghbi HY, Lee CC, Tsien RW. Increased expression of alpha 1A Ca2+ channel currents arising from expanded trinucleotide repeats in spinocerebellar ataxia type 6. J Neurosci. 2001;21:9185–9193. [PubMed]
112. Watase K, Barrett CF, Miyazaki T, Ishiguro T, Ishikawa K, Hu Y, Unno T, Sun Y, Kasai S, Watanabe M, Gomez CM, Mizusawa H, Tsien RW, Zoghbi HY. Spinocerebellar ataxia type 6 knockin mice develop a progressive neuronal dysfunction with age-dependent accumulation of mutant CaV2.1 channels. Proc Natl Acad Sci USA. 2008;105:11987–11992. [PubMed]
113. Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, Stevanin G, Durr A, Zuhlke C, Burk K, Clark HB, Brice A, Rothstein JD, Schut LJ, Day JW, Ranum LP. Spectrin mutations cause spinocerebellar ataxia type 5. Nat Genet. 2006;38:184–190. [PubMed]
114. Kose A, Saito N, Ito H, Kikkawa U, Nishizuka Y, Tanaka C. Electron microscopic localization of type I protein kinase C in rat Purkinje cells. J Neurosci. 1988;8:4262–4268. [PubMed]
115. Adachi N, Kobayashi T, Takahashi H, Kawasaki T, Shirai Y, Ueyama T, Matsuda T, Seki T, Sakai N, Saito N. Enzymological analysis of mutant protein kinase Cgamma causing spinocerebellar ataxia type 14 and dysfunction in Ca2+ homeostasis. J Biol Chem. 2008;283:19854–19863. [PubMed]
116. Zhu LP, Yu XD, Ling S, Brown RA, Kuo TH. Mitochondrial Ca(2+)homeostasis in the regulation of apoptotic and necrotic cell deaths. Cell Calcium. 2000;28:107–117. [PubMed]
117. van de Leemput J, Chandran J, Knight MA, Holtzclaw LA, Scholz S, Cookson MR, Houlden H, Gwinn-Hardy K, Fung HC, Lin X, Hernandez D, Simon-Sanchez J, Wood NW, Giunti P, Rafferty I, Hardy J, Storey E, Gardner RJ, Forrest SM, Fisher EM, Russell JT, Cai H, Singleton AB. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet. 2007;3:e108. [PubMed]
118. Miyoshi Y, Yamada T, Tanimura M, Taniwaki T, Arakawa K, Ohyagi Y, Furuya H, Yamamoto K, Sakai K, Sasazuki T, Kira J. A novel autosomal dominant spinocerebellar ataxia (SCA16) linked to chromosome 8q22.1–24.1. Neurology. 2001;57:96–100. [PubMed]
119. Miura S, Shibata H, Furuya H, Ohyagi Y, Osoegawa M, Miyoshi Y, Matsunaga H, Shibata A, Matsumoto N, Iwaki A, Taniwaki T, Kikuchi H, Kira J, Fukumaki Y. The contactin 4 gene locus at 3p26 is a candidate gene of SCA16. Neurology. 2006;67:1236–1241. [PubMed]
120. Tanaka E, Maruyama H, Morino H, Nakajima E, Kawakami H. The CNTN4 c.4256C > T mutation is rare in Japanese with inherited spinocerebellar ataxia. J Neurol Sci. 2008;266:180–181. [PubMed]
121. Hisatsune C, Kuroda Y, Akagi T, Torashima T, Hirai H, Hashikawa T, Inoue T, Mikoshiba K. Inositol 1,4,5-trisphosphate receptor type 1 in granule cells, not in Purkinje cells, regulates the dendritic morphology of Purkinje cells through brain-derived neurotrophic factor production. J Neurosci. 2006;26:10916–10924. [PubMed]
122. Inoue T, Kato K, Kohda K, Mikoshiba K. Type 1 inositol 1,4,5-trisphosphate receptor is required for induction of long-term depression in cerebellar Purkinje neurons. J Neurosci. 1998;18:5366–5373. [PubMed]
123. Fujii S, Matsumoto M, Igarashi K, Kato H, Mikoshiba K. Synaptic plasticity in hippocampal CA1 neurons of mice lacking type 1 inositol-1,4,5-trisphosphate receptors. Learn Mem. 2000;7:312–320. [PubMed]
124. Nagase T, Ito KI, Kato K, Kaneko K, Kohda K, Matsumoto M, Hoshino A, Inoue T, Fujii S, Kato H, Mikoshiba K. Long-term potentiation and long-term depression in hippocampal CA1 neurons of mice lacking the IP(3) type 1 receptor. Neuroscience. 2003;117:821–830. [PubMed]
125. Harper SQ, Staber PD, He X, Eliason SL, Martins IH, Mao Q, Yang L, Kotin RM, Paulson HL, Davidson BL. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc Natl Acad Sci USA. 2005;102:5820–5825. [PubMed]
126. Xia H, Mao Q, Eliason SL, Harper SQ, Martins IH, Orr HT, Paulson HL, Yang L, Kotin RM, Davidson BL. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med. 2004;10:816–820. [PubMed]
127. Hu J, Matsui M, Gagnon KT, Schwartz JC, Gabillet S, Arar K, Wu J, Bezprozvanny I, Corey DR. Allele-specific silencing of mutant huntingtin and ataxin-3 genes by targeting expanded CAG repeats in mRNAs. Nat Biotechnol. 2009;27:478–484. [PMC free article] [PubMed]
128. Shao J, Diamond MI. Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Hum Mol Genet. 2007;16(2):R115–R123. [PubMed]
129. Warrick JM, Chan HY, Gray-Board GL, Chai Y, Paulson HL, Bonini NM. Suppression of polyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Nat Genet. 1999;23:425–428. [PubMed]
130. Wyttenbach A, Sauvageot O, Carmichael J, Diaz-Latoud C, Arrigo AP, Rubinsztein DC. Heat shock protein 27 prevents cellular polyglutamine toxicity and suppresses the increase of reactive oxygen species caused by huntingtin. Hum Mol Genet. 2002;11:1137–1151. [PubMed]
131. Wacker JL, Zareie MH, Fong H, Sarikaya M, Muchowski PJ. Hsp70 and Hsp40 attenuate formation of spherical and annular polyglutamine oligomers by partitioning monomer. Nat Struct Mol Biol. 2004;11:1215–1222. [PubMed]
132. Heiser V, Engemann S, Brocker W, Dunkel I, Boeddrich A, Waelter S, Nordhoff E, Lurz R, Schugardt N, Rautenberg S, Herhaus C, Barnickel G, Bottcher H, Lehrach H, Wanker EE. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc Natl Acad Sci USA. 2002;99(Suppl 4):16400–16406. [PubMed]
133. Sanchez I, Mahlke C, Yuan J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature. 2003;421:373–379. [PubMed]
134. Zhang X, Smith DL, Meriin AB, Engemann S, Russel DE, Roark M, Washington SL, Maxwell MM, Marsh JL, Thompson LM, Wanker EE, Young AB, Housman DE, Bates GP, Sherman MY, Kazantsev AG. A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci USA. 2005;102:892–897. [PubMed]
135. Wang J, Gines S, MacDonald ME, Gusella JF. Reversal of a full-length mutant huntingtin neuronal cell phenotype by chemical inhibitors of polyglutamine-mediated aggregation. BMC Neurosci. 2005;6:1. [PMC free article] [PubMed]
136. Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum Mol Genet. 2006;15:2743–2751. [PubMed]
137. Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, Hersch S. A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2–8 in the R6/2 transgenic mouse. Proc Natl Acad Sci USA. 2007;104:16685–16689. [PubMed]
138. Nagai Y, Tucker T, Ren H, Kenan DJ, Henderson BS, Keene JD, Strittmatter WJ, Burke JR. Inhibition of polyglutamine protein aggregation and cell death by novel peptides identified by phage display screening. J Biol Chem. 2000;275:10437–10442. [PubMed]
139. Nagai Y, Fujikake N, Ohno K, Higashiyama H, Popiel HA, Rahadian J, Yamaguchi M, Strittmatter WJ, Burke JR, Toda T. Prevention of polyglutamine oligomerization and neurodegeneration by the peptide inhibitor QBP1 in Drosophila. Hum Mol Genet. 2003;12:1253–1259. [PubMed]
140. Popiel HA, Nagai Y, Fujikake N, Toda T. Protein transduction domain-mediated delivery of QBP1 suppresses polyglutamine-induced neurodegeneration in vivo. Mol Ther. 2007;15:303–309. [PubMed]
141. Popiel HA, Nagai Y, Fujikake N, Toda T. Delivery of the aggregate inhibitor peptide QBP1 into the mouse brain using PTDs and its therapeutic effect on polyglutamine disease mice. Neurosci Lett. 2009;449:87–92. [PubMed]
142. Kim MW, Chelliah Y, Kim SW, Otwinowski Z, Bezprozvanny I. Secondary structure of Huntingtin amino-terminal region. Structure. 2009;17:1205–1212. [PMC free article] [PubMed]
143. Lee ST, Chu K, Park JE, Kang L, Ko SY, Jung KH, Kim M. Memantine reduces striatal cell death with decreasing calpain level in 3-nitropropionic model of Huntington's disease. Brain Res. 2006;1118:199–207. [PubMed]
144. Landwehrmeyer GB, Dubois B, de Yebenes JG, Kremer B, Gaus W, Kraus PH, Przuntek H, Dib M, Doble A, Fischer W, Ludolph AC. Riluzole in Huntington's disease: a 3-year, randomized controlled study. Ann Neurol. 2007;62:262–272. [PubMed]
145. Chan CS, Guzman JN, Ilijic E, Mercer JN, Rick C, Tkatch T, Meredith GE, Surmeier DJ. ‘Rejuvenation’ protects neurons in mouse models of Parkinson's disease. Nature. 2007;447:1081–1086. [PubMed]
146. Becker C, Jick SS, Meier CR. Use of antihypertensives and the risk of Parkinson disease. Neurology. 2008;70:1438–1444. [PubMed]
147. Chaturvedi RK, Beal MF. Mitochondrial approaches for neuroprotection. Ann N Y Acad Sci. 2008;1147:395–412. [PMC free article] [PubMed]