Search tips
Search criteria

Results 1-25 (666869)

Clipboard (0)

Related Articles

1.  Stimulation of autophagy reduces neurodegeneration in a mouse model of human tauopathy 
Brain  2012;135(7):2169-2177.
The accumulation of insoluble proteins is a pathological hallmark of several neurodegenerative disorders. Tauopathies are caused by the dysfunction and aggregation of tau protein and an impairment of cellular protein degradation pathways may contribute to their pathogenesis. Thus, a deficiency in autophagy can cause neurodegeneration, while activation of autophagy is protective against some proteinopathies. Little is known about the role of autophagy in animal models of human tauopathy. In the present report, we assessed the effects of autophagy stimulation by trehalose in a transgenic mouse model of tauopathy, the human mutant P301S tau mouse, using biochemical and immunohistochemical analyses. Neuronal survival was evaluated by stereology. Autophagy was activated in the brain, where the number of neurons containing tau inclusions was significantly reduced, as was the amount of insoluble tau protein. This reduction in tau aggregates was associated with improved neuronal survival in the cerebral cortex and the brainstem. We also observed a decrease of p62 protein, suggesting that it may contribute to the removal of tau inclusions. Trehalose failed to activate autophagy in the spinal cord, where it had no impact on the level of sarkosyl-insoluble tau. Accordingly, trehalose had no effect on the motor impairment of human mutant P301S tau transgenic mice. Our findings provide direct evidence in favour of the degradation of tau aggregates by autophagy. Activation of autophagy may be worth investigating in the context of therapies for human tauopathies.
PMCID: PMC3381726  PMID: 22689910
autophagy; neurodegenerative disorders; neuroprotection; protein aggregation; tau
2.  Heat Shock Protein 70 Prevents both Tau Aggregation and the Inhibitory Effects of Preexisting Tau Aggregates on Fast Axonal Transport 
Biochemistry  2011;50(47):10300-10310.
Aggregation and accumulation of the microtubule-associated protein tau are associated with cognitive decline and neuronal degeneration in Alzheimer's disease and other tauopathies. Thus, preventing the transition of tau from a soluble state to insoluble aggregates and/or reversing the toxicity of existing aggregates would represent a reasonable therapeutic strategy for treating these neurodegenerative diseases. Here we demonstrate that molecular chaperones of the heat shock protein 70 (Hsp70) family are potent inhibitors of tau aggregation in vitro, preventing the formation of both mature fibrils and oligomeric intermediates. Remarkably, addition of Hsp70 to a mixture of oligomeric and fibrillar tau aggregates prevents the toxic effect of these tau species on fast axonal transport, a critical process for neuronal function. When incubated with preformed tau aggregates, Hsp70 preferentially associated with oligomeric over fibrillar tau, suggesting that prefibrillar oligomeric tau aggregates play a prominent role in tau toxicity. Taken together, our data provide a novel molecular basis for the protective effect of Hsp70 in tauopathies.
PMCID: PMC3387688  PMID: 22039833
Acta neuropathologica  2012;124(2):153-172.
Protein misfolding, aggregation and deposition are common disease mechanisms in many neurodegenerative diseases including Parkinson’s disease. Accumulation of damaged or abnormally modified proteins may lead to perturbed cellular function and eventually to cell death. Thus neurons rely on elaborated pathways of protein quality control and removal to maintain intracellular protein homeostasis. Molecular chaperones, the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP) are critical pathways that mediate the refolding or removal of abnormal proteins.
The successive failure of these protein degradation pathways, as a cause or consequence of early pathological alterations in vulnerable neurons at risk, may present a key step in the pathological cascade that leads to spreading neurodegeneration. A growing number of studies in disease models and patients have implicated dysfunction of the UPS and ALP in the pathogenesis of Parkinson’s disease and related disorders. Deciphering the exact mechanism by which the different proteolytic systems contribute to the elimination of pathogenic proteins, like α-synuclein, is therefore of paramount importance. We herein review the role of protein degradation pathways in Parkinson’s disease and elaborate on the different contributions of the UPS and the ALP to the clearance of altered proteins. We examine the interplay between different degradation pathways and provide a model for the role of the UPS and ALP in the evolution and progression of α-synuclein pathology. With regards to exciting recent studies we also discuss the putative potential of using protein degradation pathways as novel therapeutic targets in Parkinson’s disease.
PMCID: PMC3417142  PMID: 22744791
Parkinson’s disease; neurodegeneration; α-synuclein; autophagy; lysosome; ubiquitin-proteasome system; molecular chaperones
4.  Intracellular degradation of misfolded proteins in polyglutamine neurodegenerative diseases 
Brain research reviews  2008;59(1):245-252.
A number of neurodegenerative diseases, including Alzheimer’s, Parkinson’s, and polyglutamine diseases, are characterized by the age-dependent formation of intracellular protein aggregates and neurodegeneration. Although there is some debate surrounding the role of these aggregates in neurotoxicity, the formation of aggregates is known to reflect the accumulation of misfolded and toxic proteins. The degradation of misfolded proteins occurs mainly via the ubiquitin–proteasome and autophagy pathways. In neuronal cells, polyglutamine protein inclusions are present predominantly in the nucleus, which is not accessible to autophagy. It remains unclear how the ubiquitin–proteasomal and autophagy pathways remove misfolded proteins in the different subcellular regions of neurons, where disease proteins become misfolded and aggregated in an age-dependent manner. Here we discuss the key findings to date about the roles of the ubiquitin–proteasome system and autophagy in polyglutamine diseases. Understanding how these two pathways function to clear mutant polyglutamine proteins will further the development of effective treatments for polyglutamine and other neurodegenerative diseases.
PMCID: PMC2577582  PMID: 18773920
Ubiquitin; Proteasome; Autophagy; Polyglutamine; Huntingtin; Neurodegeneration
5.  Approaches for probing the sequence space of substrates recognized by molecular chaperones 
Methods (San Diego, Calif.)  2010;53(3):318-324.
Neurodegeneration, the progressive loss of function in neurons that eventually leads to their death, is the cause of many neurodegenerative disorders including Alzheimer’s, Parkinson’s, and Huntington’s diseases. Protein aggregation is a hallmark of most neurodegenerative diseases, where unfolded proteins form intranuclear, cytosolic, and extracellular insoluble aggregates in neurons. Mounting evidence from studies in neurodegenerative disease models shows that molecular chaperones, key regulators of protein aggregation and degradation, play critical roles in the progression of neurodegeneration. Although chaperones exhibit promiscuity in their substrate specificity, specific molecular features are required for substrate recognition. Understanding the basis for substrate recognition by chaperones will aid in the development of therapeutic strategies that regulate chaperone expression levels in order to combat neurodegeneration. Many experimental techniques, including alanine scanning mutagenesis and phage display library screening, have been developed and applied to understand the basis of substrate recognition by chaperones. Here, we present computational algorithms that can be applied to rapidly screen the sequence space of potential substrates to determine the sequence and structural requirements for substrate recognition by chaperones.
PMCID: PMC3057280  PMID: 21195183
6.  The Characterization of Microtubule-Stabilizing Drugs as Possible Therapeutic Agents for Alzheimer’s Disease and Related Tauopathies 
Tau, a protein that is enriched in neurons of the central nervous system (CNS)1, is thought to play a critical role in the stabilization of microtubules (MTs). Several neurodegenerative disorders referred to as tauopathies, including Alzheimer’s disease and certain types of frontotemporal lobar degeneration, are characterized by the intracellular accumulation of hyperphosphorylated tau fibrils. Tau deposition into insoluble aggregates is believed to result in a loss of tau function that leads to MT destabilization, and this could cause neurodegeneration as intact MTs are required for axonal transport and normal neuron function. This tau loss-of-function hypothesis has been validated in a tau transgenic mouse model with spinal cord tau inclusions, where the MT-stabilizing agent, paclitaxel, increased spinal nerve MT density and improved motor function after drug absorption at neuromuscular junctions. Unfortunately, paclitaxel is a P-glycoprotein substrate and has poor blood-brain barrier permeability, making it unsuitable for the treatment of human tauopathies. We therefore examined several MT-stabilizing compounds from the taxane and epothilone natural product families to assess their membrane permeability and to determine whether they act as substrates or inhibitors of P-glycoprotein. Moreover, we compared brain and plasma levels of the compounds after administration to mice. Finally, we assessed whether brain-penetrant compounds could stabilize mouse CNS MTs. We found that several epothilones have significantly greater brain penetration than the taxanes. Furthermore, certain epothilones cause an increase in CNS MT stabilization, with epothilone D demonstrating a favorable pharmacokinetic and pharmacodynamic profile which suggests this agent merits further study as a potential tauopathy drug candidate.
PMCID: PMC3042036  PMID: 21163349
Alzheimer’s disease; microtubules; tauopathies; therapeutic
7.  Autophagic failure promotes the exocytosis and intercellular transfer of α-synuclein 
The accumulation of abnormal protein aggregates is a major characteristic of many neurodegenerative disorders, including Parkinson's disease (PD). The intracytoplasmic deposition of α-synuclein aggregates and Lewy bodies, often found in PD and other α-synucleinopathies, is thought to be linked to inefficient cellular clearance mechanisms, such as the proteasome and autophagy/lysosome pathways. The accumulation of α-synuclein aggregates in neuronal cytoplasm causes numerous autonomous changes in neurons. However, it can also affect the neighboring cells through transcellular transmission of the aggregates. Indeed, a progressive spreading of Lewy pathology among brain regions has been hypothesized from autopsy studies. We tested whether inhibition of the autophagy/lysosome pathway in α-synuclein-expressing cells would increase the secretion of α-synuclein, subsequently affecting the α-synuclein deposition in and viability of neighboring cells. Our results demonstrated that autophagic inhibition, via both pharmacological and genetic methods, led to increased exocytosis of α-synuclein. In a mixed culture of α-synuclein-expressing donor cells with recipient cells, autophagic inhibition resulted in elevated transcellular α-synuclein transmission. This increase in protein transmission coincided with elevated apoptotic cell death in the recipient cells. These results suggest that the inefficient clearance of α-synuclein aggregates, which can be caused by reduced autophagic activity, leads to elevated α-synuclein exocytosis, thereby promoting α-synuclein deposition and cell death in neighboring neurons. This finding provides a potential link between autophagic dysfunction and the progressive spread of Lewy pathology.
PMCID: PMC3674407  PMID: 23661100
autophagy; neurodegeneration; protein aggregation; signal transduction
8.  Autophagy and misfolded proteins in neurodegeneration 
Experimental Neurology  2012;238(1):22-28.
The accumulation of misfolded proteins in insoluble aggregates within the neuronal cytoplasm is one of the common pathological hallmarks of most adult-onset human neurodegenerative diseases. The clearance of these misfolded proteins may represent a promising therapeutic strategy in these diseases. The two main routes for intracellular protein degradation are the ubiquitin–proteasome and the autophagy–lysosome pathways. In this review, we will focus on the autophagic pathway, by providing some examples of how impairment at different steps in this degradation pathway is related to different neurodegenerative diseases. We will also consider that upregulating autophagy may be useful in the treatment of some of these diseases. Finally, we discuss how antioxidants, which have been considered to be beneficial in neurodegenerative diseases, can block autophagy, thus potentially compromising their therapeutic potential.
Research highlights
►Autophagy compromise occurs in different neurodegenerative diseases. ►Upregulating autophagy may be useful in the treatment of some neurodegenerative diseases. ►Many different reactive oxygen species scavengers impair autophagy
PMCID: PMC3463804  PMID: 21095248
Autophagy; Neurodegeneration; Huntington's disease
9.  The Co-chaperone BAG2 Sweeps PHF Insoluble Tau from the Microtubule 
Tau inclusions are a prominent feature of many neurodegenerative diseases including Alzheimer’s disease. Their accumulation in neurons as ubiquitinated filaments suggests a failure in the degradation limb of the Tau pathway. The components of a Tau protein triage system consisting of CHIP/Hsp70 and other chaperones have begun to emerge. However, the site of triage and the master regulatory elements are unknown. Here we report an elegant mechanism of Tau degradation involving the co-chaperone BAG2. The BAG2/Hsp70 complex is tethered to the microtubule and this complex can capture and deliver Tau to the proteasome for ubiquitin-independent degradation. This complex preferentially degrades sarkosyl insoluble Tau and phosphorylated Tau. BAG2 levels in cells are under the physiological control of the microRNA miR-128a, which can tune PHF Tau levels in neurons. Thus we propose that ubiquitinated Tau inclusions arise due to shunting of Tau degradation toward a less efficient ubiquitin-dependent pathway.
PMCID: PMC2768429  PMID: 19228967
BCL-Associated anthanogene2 (BAG2); Heat Shock Protein70 (Hsp 70); Phosphorylated Tau; ubiquitin; proteasome; mir-128a
10.  Autophagy impairment: a crossroad between neurodegeneration and tauopathies 
BMC Biology  2012;10:78.
Most neurodegenerative diseases involve the accumulation of misfolded proteins in the nervous system. Impairment of protein degradation pathways such as autophagy is emerging as a consistent and transversal pathological phenomenon in neurodegenerative diseases, including Alzheimer's, Huntington's, and Parkinson's disease. Genetic inactivation of autophagy in mice has demonstrated a key role of the pathway in maintaining protein homeostasis in the brain, triggering massive neuronal loss and the accumulation of abnormal protein inclusions. However, the mechanism underlying neurodegeneration due to autophagy impairment remains elusive. A paper in Molecular Neurodegeneration from Abeliovich's group now suggests a role for phosphorylation of Tau and the activation of glycogen synthase kinase 3β (GSK3β) in driving neurodegeneration in autophagy-deficient neurons. We discuss the implications of this study for understanding the factors driving neurofibrillary tangle formation in Alzheimer's disease and tauopathies.
See research article
PMCID: PMC3448508  PMID: 22999309
11.  Proteinopathy-induced neuronal senescence: a hypothesis for brain failure in Alzheimer's and other neurodegenerative diseases 
Alzheimer's disease (AD) and a host of other neurodegenerative central nervous system (CNS) proteinopathies are characterized by the accumulation of misfolded protein aggregates. Simplistically, these aggregates can be divided into smaller, soluble, oligomeric and larger, less-soluble or insoluble, fibrillar forms. Perhaps the major ongoing debate in the neurodegenerative disease field is whether the smaller oligomeric or larger fibrillar aggregates are the primary neurotoxin. Herein, we propose an integrative hypothesis that provides new insights into how a variety of misfolded protein aggregates can result in neurodegeneration.
We introduce the concept that a wide range of highly stable misfolded protein aggregates in AD and other neurodegenerative proteinopathies are recognized as non-self and chronically activate the innate immune system. This pro-inflammatory state leads to physiological senescence of CNS cells. Once CNS cells undergo physiological senescence, they secrete a variety of pro-inflammatory molecules. Thus, the senescence of cells, which was initially triggered by inflammatory stimuli, becomes a self-reinforcing stimulus for further inflammation and senescence. Ultimately, senescent CNS cells become functionally impaired and eventually die, and this neurodegeneration leads to brain organ failure.
This integrative hypothesis, which we will refer to as the proteinopathy-induced senescent cell hypothesis of AD and other neurodegenerative diseases, links CNS proteinopathies to inflammation, physiological senescence, cellular dysfunction, and ultimately neurodegeneration. Future studies characterizing the senescent phenotype of CNS cells in AD and other neurodegenerative diseases will test the validity of this hypothesis. The implications of CNS senescence as a contributing factor to the neurodegenerative cascade and its implications for therapy are discussed.
PMCID: PMC2874257  PMID: 19822029
12.  Molecular chaperones and regulation of tau quality control: strategies for drug discovery in tauopathies 
Future medicinal chemistry  2011;3(12):1523-1537.
Tau is a microtubule-associated protein that accumulates in at least 15 different neurodegenerative disorders, which are collectively referred to as tauopathies. In these diseases, tau is often hyperphosphorylated and found in aggregates, including paired helical filaments, neurofibrillary tangles and other abnormal oligomers. Tau aggregates are associated with neuron loss and cognitive decline, which suggests that this protein can somehow evade normal quality control allowing it to aberrantly accumulate and become proteotoxic. Consistent with this idea, recent studies have shown that molecular chaperones, such as heat shock protein 70 and heat shock protein 90, counteract tau accumulation and neurodegeneration in disease models. These molecular chaperones are major components of the protein quality control systems and they are specifically involved in the decision to retain or degrade many proteins, including tau and its modified variants. Thus, one potential way to treat tauopathies might be to either accelerate interactions of abnormal tau with these quality control factors or tip the balance of triage towards tau degradation. In this review, we summarize recent findings and suggest models for therapeutic intervention.
PMCID: PMC3190966  PMID: 21882945
13.  Changes in dendritic complexity and spine morphology in transgenic mice expressing human wild-type tau 
Brain structure & function  2010;214(2-3):161-179.
Neurofibrillary tangles (NFTs) are composed of insoluble, hyperphosphorylated aggregates of the microtubule-associated protein tau and are present in various neurodegenerative diseases, including Alzheimer’s disease (AD). To investigate how tau affects neuronal function during NFT formation and subsequent neurodegeneration, we examined the morphology, spine density, spine type, and spine volume of layer III pyramidal neurons from the prefrontal cortex of mice expressing wild-type human tau (htau) over time. There were no significant alterations in apical dendritic arbor length in 3-, 6-, and 12-month-old htau mice; however, 12-month-old mice exhibited more complex arborization patterns. In addition, we observed a shift in spine morphology with fewer mushroom and more thin spines in both apical and basal dendrites as a function of htau accumulation. Interestingly, there was an overall decrease in volume of spines from 3 to 12 months. However, the volume of mushroom spines decreased from 3 to 6 months and increased from 6 to 12 months. This increase in complexity and branching in 12-month-old mice and the increase of volume of mushroom spines may represent compensatory mechanisms in the remaining intact neurons. As such, the accumulation of phosphorylated tau over time may contribute to the cognitive decline observed in AD by affecting neuronal structure and synaptic properties. Such alterations in dendrites and spines may result in the deterioration of neuronal function observed in AD, and provide a morphologic substrate for the relationship between synaptic integrity and cognitive decline.
PMCID: PMC3032082  PMID: 20213269
Alzheimer’s disease; Neurofibrillary tangles; Tau; Transgenic mice; Dendrites; Spines
14.  Hsp40 Gene Therapy Exerts Therapeutic Effects on Polyglutamine Disease Mice via a Non-Cell Autonomous Mechanism 
PLoS ONE  2012;7(11):e51069.
The polyglutamine (polyQ) diseases such as Huntington’s disease (HD), are neurodegenerative diseases caused by proteins with an expanded polyQ stretch, which misfold and aggregate, and eventually accumulate as inclusion bodies within neurons. Molecules that inhibit polyQ protein misfolding/aggregation, such as Polyglutamine Binding Peptide 1 (QBP1) and molecular chaperones, have been shown to exert therapeutic effects in vivo by crossing of transgenic animals. Towards developing a therapy using these aggregation inhibitors, we here investigated the effect of viral vector-mediated gene therapy using QBP1 and molecular chaperones on polyQ disease model mice. We found that injection of adeno-associated virus type 5 (AAV5) expressing QBP1 or Hsp40 into the striatum both dramatically suppresses inclusion body formation in the HD mouse R6/2. AAV5-Hsp40 injection also ameliorated the motor impairment and extended the lifespan of R6/2 mice. Unexpectedly, we found even in virus non-infected cells that AAV5-Hsp40 appreciably suppresses inclusion body formation, suggesting a non-cell autonomous therapeutic effect. We further show that Hsp40 inhibits secretion of the polyQ protein from cultured cells, implying that it inhibits the recently suggested cell-cell transmission of the polyQ protein. Our results demonstrate for the first time the therapeutic effect of Hsp40 gene therapy on the neurological phenotypes of polyQ disease mice.
PMCID: PMC3511362  PMID: 23226463
15.  Signaling, Polyubiquitination, Trafficking, and Inclusions: Sequestosome 1/p62's Role in Neurodegenerative Disease 
Aggregated misfolded proteins are hallmarks of most neurodegenerative diseases. In a chronic disease state, including pathologic situations of oxidative stress, these proteins are sequestered into inclusions. Accumulation of aggregated proteins can be prevented by chaperones, or by targeting their degradation to the UPS. If the accumulation of these proteins exceeds their degradation, they may impair the function of the proteasome. Alternatively, the function of the proteasome may be preserved by directing aggregated proteins to the autophagy-lysosome pathway for degradation. Sequestosome 1/p62 has recently been shown to interact with polyubiquitinated proteins through its UBA domain and may direct proteins to either the UPS or autophagosome. P62 is present in neuronal inclusions of individuals with Alzheimer's disease and other neurodegenerative diseases. Herein, we review p62's role in signaling, aggregation, and inclusion formation, and specifically as a possible contributor to Alzheimer's disease. The use of p62 as a potential target for the development of therapeutics and as a disease biomarker is also discussed.
PMCID: PMC1559922  PMID: 17047309
16.  Parkinson's Disease and Autophagy 
Parkinson's Disease  2012;2012:429524.
It is generally accepted that a correlation between neurodegenerative disease and protein aggregation in the brain exists; however, a causal relationship has not been elucidated. In neurons, failure of autophagy may result in the accumulation of aggregate-prone proteins and subsequent neurodegeneration. Thus, pharmacological induction of autophagy to enhance the clearance of intracytoplasmic aggregate-prone proteins has been considered as a therapeutic strategy to ameliorate pathology in cell and animal models of neurodegenerative disorders. However, autophagy has also been found to be a factor in the onset of these diseases, which raises the question of whether autophagy induction is an effective therapeutic strategy, or, on the contrary, can result in cell death. In this paper, we will first describe the autophagic machinery, and we will consider the literature to discuss the neuroprotective effects of autophagy.
PMCID: PMC3483737  PMID: 23125941
17.  Autophagy and polyglutamine diseases 
Progress in Neurobiology  2012;97(2):67-82.
► The ubiquitin–proteasome system and autophagy are two main degradative pathways. ► Autophagy upregulation may protect against polyglutamine-expanded protein neurotoxicity. ► Autophagy compromise may occur in certain neurodegenerative diseases.
In polyglutamine diseases, an abnormally elongated polyglutamine tract results in protein misfolding and accumulation of intracellular aggregates. The length of the polyglutamine expansion correlates with the tendency of the mutant protein to aggregate, as well as with neuronal toxicity and earlier disease onset. Although currently there is no effective cure to prevent or slow down the progression of these neurodegenerative disorders, increasing the clearance of mutant proteins has been proposed as a potential therapeutic approach. The ubiquitin–proteasome system and autophagy are the two main degradative pathways responsible for eliminating misfolded and unnecessary proteins in the cell. We will review some of the studies that have proposed autophagy as a strategy to reduce the accumulation of polyglutamine-expanded protein aggregates and protect against mutant protein neurotoxicity. We will also discuss some of the currently known mechanisms that induce autophagy, which may be beneficial for the treatment of these and other neurodegenerative disorders.
PMCID: PMC3712188  PMID: 21930185
HD, Huntington's disease; SCA, spinocerebellar ataxia; DRPLA, Denatorubral-pallidoluysian atrophy; SBMA, spinal and bulbar muscular atropy; Htt, Huntingtin; UPS, ubiquitin–proteasome system; HDL-2, Huntington's disease-like 2; IBs, inclusion bodies; RNAi, RNA interference; Atg, autophagy-related genes; ER, endoplasmic reticulum; PI3K, phosphatidylinositol 3-kinase; JNK1, c-Jun N-terminal protein kinase 1; PE, phosphatidylethanolamine; SNAREs, soluble N-ethylmaleimide-sensitive factor attachment protein receptors; mTOR, mammalian target of rapamycin; PI-3-P, phosphatidylinositol-3-phosphate; ROS, reactive oxygen species; IP3, inositol-1,4,5-triphosphate; IP3R, IP3 receptors; cAMP, cyclic AMP; IMPase, inositol monophosphatase; GSK3β, glycogen synthase kinase-3 β; I1R, imidazoline-1-receptor; SMERs, small molecule enhancers of rapamycin; SMIRs, small molecule inhibitors of rapamycin; Polyglutamine diseases; Autophagy; Neurodegeneration; Huntington's disease
18.  Neuroprotective Activity and Evaluation of Hsp90 Inhibitors In An Immortalized Neuronal Cell Line 
Bioorganic & medicinal chemistry  2008;17(4):1709-1715.
Alzheimer’s disease (AD) neuropathology is characterized by loss of synapses and neurons, neuritic plaques consisting of β-amyloid (Aβ) peptides, and neurofibrillary tangles consisting of intracellular aggregates of hyperphosphorylated tau protein in susceptible brain regions. Aβ oligomers trigger a cascade of pathogenic events including tau hyperphosphorylation and aggregation, inflammatory reactions, and excitotoxicity that contribute to the progression of AD. The molecular chaperone Hsp90 facilitates the folding of newly synthesized and denatured proteins and is believed to play a role in neurodegenerative disorders in which the defining pathology results in misfolded proteins and the accumulation of protein aggregates. Some agents that inhibit Hsp90 protect neurons against Aβ toxicity and tau aggregation, and assays for rapidly screening potential Hsp90 inhibitors are of interest. We used the release of the soluble cytosolic enzyme lactate dehydrogenase (LDH) as an indicator of the loss of cell membrane integrity and cytotoxicity resulting from exposure to Aβ peptides to evaluate the neuroprotective properties of novel novobiocin analogues and established Hsp90 inhibitors. Compounds were assessed for potency in protecting proliferating and differentiated SH-SY5Y neuronal cells against Aβ-induced cell death; the potential of each agent alone was also determined. The data indicated that several of the compounds decreased Aβ toxicity even at low nanomolar concentrations and, unexpectedly, were more potent in protecting the undifferentiated cells against Aβ. The novobiocin analogues alone were not toxic even up to 10 μM concentrations whereas GDA and the parent compound, novobiocin, were toxic at 1 and 10 μM, respectively. The results suggest that novobiocin analogues may provide novel leads for the development of neuroprotective drugs.
PMCID: PMC2729088  PMID: 19138859
19.  Autophagy, a guardian against neurodegeneration 
Autophagy is an intracellular degradation process responsible for the clearance of most long-lived proteins and organelles. Cytoplasmic components are enclosed by double-membrane autophagosomes, which subsequently fuse with lysosomes for degradation. Autophagy dysfunction may contribute to the pathology of various neurodegenerative disorders, which manifest abnormal protein accumulation. As autophagy induction enhances the clearance of aggregate-prone intracytoplasmic proteins that cause neurodegeneration (like mutant huntingtin, tau and ataxin 3) and confers cytoprotective roles in cell and animal models, upregulating autophagy may be a tractable therapeutic strategy for diseases caused by such proteins. Here, we will review the molecular machinery of autophagy and its role in neurodegenerative diseases. Drugs and associated signalling pathways that may be targeted for pharmacological induction of autophagy will also be discussed.
PMCID: PMC2938570  PMID: 20188203
Autophagy; Alzheimer disease; Neurodegeneration; Huntington disease
20.  Molecular Chaperones as Rational Drug Targets for Parkinson’s Disease Therapeutics 
Parkinson’s disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinson’s disease and of genetic susceptibility variants for idiopathic Parkinson’s disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the co-chaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinson’s disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinson’s disease.
PMCID: PMC3364514  PMID: 20942788
Bcl-2 associated athanogene (BAG) family; C-terminal Hsp70 interacting protein (CHIP); chaperones; co-chaperones; heat shock protein (Hsp); Hsp90 inhibitors; neurodegeneration; Parkinson’s disease
21.  Loss of Hsp110 Leads to Age-Dependent Tau Hyperphosphorylation and Early Accumulation of Insoluble Amyloid β▿ †  
Molecular and Cellular Biology  2010;30(19):4626-4643.
Accumulation of tau into neurofibrillary tangles is a pathological consequence of Alzheimer's disease and other tauopathies. Failures of the quality control mechanisms by the heat shock proteins (Hsps) positively correlate with the appearance of such neurodegenerative diseases. However, in vivo genetic evidence for the roles of Hsps in neurodegeneration remains elusive. Hsp110 is a nucleotide exchange factor for Hsp70, and direct substrate binding to Hsp110 may facilitate substrate folding. Hsp70 complexes have been implicated in tau phosphorylation state and amyloid precursor protein (APP) processing. To provide evidence for a role for Hsp110 in central nervous system homeostasis, we have generated hsp110−/− mice. Our results show that hsp110−/− mice exhibit accumulation of hyperphosphorylated-tau (p-tau) and neurodegeneration. We also demonstrate that Hsp110 is in complexes with tau, other molecular chaperones, and protein phosphatase 2A (PP2A). Surprisingly, high levels of PP2A remain bound to tau but with significantly reduced activity in brain extracts from aged hsp110−/− mice compared to brain extracts from wild-type mice. Mice deficient in the Hsp110 partner (Hsp70) also exhibit a phenotype comparable to that of hsp110−/− mice, confirming a critical role for Hsp110-Hsp70 in maintaining tau in its unphosphorylated form during aging. In addition, crossing hsp110−/− mice with mice overexpressing mutant APP (APPβsw) leads to selective appearance of insoluble amyloid β42 (Aβ42), suggesting an essential role for Hsp110 in APP processing and Aβ generation. Thus, our findings provide in vivo evidence that Hsp110 plays a critical function in tau phosphorylation state through maintenance of efficient PP2A activity, confirming its role in pathogenesis of Alzheimer's disease and other tauopathies.
PMCID: PMC2950521  PMID: 20679486
22.  Mitochondrial Turnover and Aging of Long-Lived Postmitotic Cells: The Mitochondrial–Lysosomal Axis Theory of Aging 
Antioxidants & Redox Signaling  2010;12(4):503-535.
It is now generally accepted that aging and eventual death of multicellular organisms is to a large extent related to macromolecular damage by mitochondrially produced reactive oxygen species, mostly affecting long-lived postmitotic cells, such as neurons and cardiac myocytes. These cells are rarely or not at all replaced during life and can be as old as the whole organism. The inherent inability of autophagy and other cellular-degradation mechanisms to remove damaged structures completely results in the progressive accumulation of garbage, including cytosolic protein aggregates, defective mitochondria, and lipofuscin, an intralysosomal indigestible material. In this review, we stress the importance of crosstalk between mitochondria and lysosomes in aging. The slow accumulation of lipofuscin within lysosomes seems to depress autophagy, resulting in reduced turnover of effective mitochondria. The latter not only are functionally deficient but also produce increased amounts of reactive oxygen species, prompting lipofuscinogenesis. Moreover, defective and enlarged mitochondria are poorly autophagocytosed and constitute a growing population of badly functioning organelles that do not fuse and exchange their contents with normal mitochondria. The progress of these changes seems to result in enhanced oxidative stress, decreased ATP production, and collapse of the cellular catabolic machinery, which eventually is incompatible with survival. Antioxid. Redox Signal. 12, 503–535.
ROS, Mitochondrial Damage, and Aging
Biomolecular damage under normal conditions
Imperfect turnover of damaged biologic structures
Major targets of ROS attack: mitochondria and lysosomes
Mitochondrial Fusion, Fission, and Biogenesis
The role of mitochondrial dynamics
Mitochondrial fusion
Mitochondrial fission
Mitochondrial biogenesis
Mitochondrial Proteolytic Systems
Mitochondrial Turnover by Autophagy
The main functions of the lysosomal compartment
Autophagic degradation of mitochondria (mitophagy)
Lipofuscin Formation and Its Influence on Autophagy
Influence of labile iron and ROS on lipofuscin formation
Consequences of the nondegradability of lipofuscin
Disease-related accumulation of intralysosomal and extralysosomal waste
Imperfect Mitochondrial Turnover and Postmitotic Cellular Aging
Age-related accumulation of defective mitochondria within postmitotic cells
Age-related decline in autophagy and Lon protease activity accelerates mitochondrial damage
Enlarged mitochondria are resistant to degradation and do not fuse with normal ones
Mechanisms of the age-related accumulation of mitochondria with homoplasmic mtDNA mutations
Decreased mitochondrial biogenesis in aged cells
Summary and Conclusions
PMCID: PMC2861545  PMID: 19650712
23.  Distinct α-Synuclein Strains Differentially Promote Tau Inclusions in Neurons 
Cell  2013;154(1):10.1016/j.cell.2013.05.057.
Many neurodegenerative diseases are characterized by the accumulation of insoluble protein aggregates, including neurofibrillary tangles comprised of tau in Alzheimer’s disease and Lewy bodies composed of α-synuclein in Parkinson’s disease. Moreover, different pathological proteins frequently codeposit in disease brains. To test whether aggregated α-synuclein can directly cross-seed tau fibrillization, we administered preformed α-synuclein fibrils assembled from recombinant protein to primary neurons and transgenic mice. Remarkably, we discovered two distinct strains of synthetic α-synuclein fibrils that demonstrated striking differences in the efficiency of cross-seeding tau aggregation, both in neuron cultures and in vivo. Proteinase K digestion revealed conformational differences between the two synthetic α-synuclein strains and also between sarkosyl-insoluble α-synuclein extracted from two subgroups of Parkinson’s disease brains. We speculate that distinct strains of pathological α-synuclein likely exist in neurodegenerative disease brains and may underlie the tremendous heterogeneity of synucleinopathies.
PMCID: PMC3820001  PMID: 23827677
24.  Kinesin-1 transport reductions enhance human tau hyperphosphorylation, aggregation and neurodegeneration in animal models of tauopathies 
Human Molecular Genetics  2010;19(22):4399-4408.
Neurodegeneration induced by abnormal hyperphosphorylation and aggregation of the microtubule-associated protein tau defines neurodegenerative tauopathies. Destabilization of microtubules by loss of tau function and filament formation by toxic gain of function are two mechanisms suggested for how abnormal tau triggers neuronal loss. Recent experiments in kinesin-1 deficient mice suggested that axonal transport defects can initiate biochemical changes that induce activation of axonal stress kinase pathways leading to abnormal tau hyperphosphorylation. Here we show using Drosophila and mouse models of tauopathies that reductions in axonal transport can exacerbate human tau protein hyperphosphorylation, formation of insoluble aggregates and tau-dependent neurodegeneration. Together with previous work, our results suggest that non-lethal reductions in axonal transport, and perhaps other types of minor axonal stress, are sufficient to induce and/or accelerate abnormal tau behavior characteristic of Alzheimer's disease and other neurodegenerative tauopathies.
PMCID: PMC2957317  PMID: 20817925
25.  Dopamine Oxidation and Autophagy 
Parkinson's Disease  2012;2012:920953.
The molecular mechanisms involved in the neurodegenerative process of Parkinson's disease remain unclear. Currently, there is a general agreement that mitochondrial dysfunction, α-synuclein aggregation, oxidative stress, neuroinflammation, and impaired protein degradation are involved in the neurodegeneration of dopaminergic neurons containing neuromelanin in Parkinson's disease. Aminochrome has been proposed to play an essential role in the degeneration of dopaminergic neurons containing neuromelanin by inducing mitochondrial dysfunction, oxidative stress, the formation of neurotoxic α-synuclein protofibrils, and impaired protein degradation. Here, we discuss the relationship between the oxidation of dopamine to aminochrome, the precursor of neuromelanin, autophagy dysfunction in dopaminergic neurons containing neuromelanin, and the role of dopamine oxidation to aminochrome in autophagy dysfunction in dopaminergic neurons. Aminochrome induces the following: (i) the formation of α-synuclein protofibrils that inactivate chaperone-mediated autophagy; (ii) the formation of adducts with α- and β-tubulin, which induce the aggregation of the microtubules required for the fusion of autophagy vacuoles and lysosomes.
PMCID: PMC3433151  PMID: 22966478

Results 1-25 (666869)