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1.  CHOLESTEROL AND NEURONAL SUSCEPTIBILITY TO BETA-AMYLOID TOXICITY 
Cognitive sciences  2010;5(1):35-56.
Alzheimer’s disease (AD) is a devastating neurocognitive disorder rapidly growing across the elderly population. Although few cases arise due to genetic mutations, sporadic AD is the most common form of this disease. Therefore, there is a continuing research effort to discover a unifying cause of this form of AD. To date, the only strong genetic correlate to the sporadic AD is inheritance of the apolipoprotein E4 (ApoE4) allele, whose encoded protein is involved in cholesterol transport in the central nervous system. This genetic link has prompted a series of studies on the potential molecular mechanisms by which cholesterol could modulate neuronal degeneration in the context of AD. In this review, we discussed the involvement of cholesterol in the production of the pathological hallmarks of the disease and how it might alter the susceptibility of cells to AD-related insult. Finally, we discussed the use of cholesterol-lowering drugs as a potential preventative approach in AD.
PMCID: PMC4203449  PMID: 25339981
Cholesterol; Alzheimer’s disease; beta-amyloid; statins
2.  Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations 
Parkinsonism & related disorders  2013;19(10):869-877.
Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies including leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by non-inflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene.
We studied neuropathologically verified HDLS patients with CSF1R mutations to assess Parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with Parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11).
We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of Parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations.
doi:10.1016/j.parkreldis.2013.05.013
PMCID: PMC3977389  PMID: 23787135
HDLS; CSF1R mutation; Parkinsonism; Autosomal dominant; White matter disorders
3.  TMEM106B p.T185S regulates TMEM106B protein levels: implications for frontotemporal dementia 
Journal of neurochemistry  2013;126(6):781-791.
Frontotemporal lobar degeneration (FTLD) is the second leading cause of dementia in individuals under age 65. In many patients, the predominant pathology includes neuronal cytoplasmic or intranuclear inclusions of ubiquitinated TAR DNA binding protein 43 (FTLDTDP). Recently, a genome-wide association study identified the first FTLD-TDP genetic risk factor, in which variants in and around the TMEM106B gene (top SNP rs1990622) were significantly associated with FTLD-TDP risk. Intriguingly, the most significant association was in FTLD-TDP patients carrying progranulin (GRN) mutations. Here we investigated to what extent the coding variant, rs3173615 (p.T185S) in linkage disequilibrium with rs1990622, affects progranulin protein (PGRN) biology and TMEM106B protein regulation.
First, we confirmed the association of TMEM106B variants with FTLD-TDP in a new cohort of GRN mutation carriers. We next generated and characterized a TMEM106B-specific antibody for investigation of this protein. Enzyme-linked immunoassay analysis of PGRN levels showed similar effects upon T185 and S185 TMEM106B overexpression. However, overexpression of T185 consistently led to higher TMEM106B protein levels than S185. Cycloheximide treatment experiments revealed that S185 degrades faster than T185 TMEM106B, potentially due to differences in N-glycosylation at residue N183. Together, our results provide a potential mechanism by which TMEM106B variants lead to differences in FTLD-TDP risk.
doi:10.1111/jnc.12329
PMCID: PMC3766501  PMID: 23742080
TMEM106B; frontotemporal dementia; progranulin; glycosylation
4.  CSF1R mutations link POLD and HDLS as a single disease entity 
Neurology  2013;80(11):1033-1040.
Objective:
Pigmented orthochromatic leukodystrophy (POLD) and hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) are rare neurodegenerative disorders characterized by cerebral white matter abnormalities, myelin loss, and axonal swellings. The striking overlap of clinical and pathologic features of these disorders suggested a common pathogenesis; however, no genetic or mechanistic link between POLD and HDLS has been established. Recently, we reported that mutations in the colony-stimulating factor 1 receptor (CSF1R) gene cause HDLS. In this study, we determined whether CSF1R mutations are also a cause of POLD.
Methods:
We performed sequencing of CSF1R in 2 pathologically confirmed POLD families. For the largest family (FTD368), a detailed case report was provided and brain samples from 2 affected family members previously diagnosed with POLD were re-evaluated to determine whether they had HDLS features. In vitro functional characterization of wild-type and mutant CSF1R was also performed.
Results:
We identified CSF1R mutations in both POLD families: in family 5901, we found c.2297T>C (p.M766T), previously reported by us in HDLS family CA1, and in family FTD368, we identified c.2345G>A (p.R782H), recently reported in a biopsy-proven HDLS case. Immunohistochemical examination in family FTD368 showed the typical neuronal and glial findings of HDLS. Functional analyses of CSF1R mutant p.R782H (identified in this study) and p.M875T (previously observed in HDLS), showed a similar loss of CSF1R autophosphorylation of selected tyrosine residues in the kinase domain for both mutations when compared with wild-type CSF1R.
Conclusions:
We provide the first genetic and mechanistic evidence that POLD and HDLS are a single clinicopathologic entity.
doi:10.1212/WNL.0b013e31828726a7
PMCID: PMC3653204  PMID: 23408870
5.  MRI characteristics and scoring in HDLS due to CSF1R gene mutations 
Neurology  2012;79(6):566-574.
Objective:
To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5.
Methods:
We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0−57) for each MRI scan.
Results:
Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10−33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology.
Conclusion:
Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion.
doi:10.1212/WNL.0b013e318263575a
PMCID: PMC3413763  PMID: 22843259
6.  Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis 
Neuron  2011;72(2):245-256.
SUMMARY
Several families have been reported with autosomal dominant frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), genetically linked to chromosome 9p21. Here we report an expansion of a non-coding GGGGCC hexanucleotide repeat in the gene C9ORF72 that is strongly associated with disease in a large FTD/ALS kindred, previously reported to be conclusively linked to chromosome 9p. This same repeat expansion was identified in the majority of our families with a combined FTD/ALS phenotype and TDP-43 based pathology. Analysis of extended clinical series found the C9ORF72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (22.5%). The repeat expansion leads to the loss of one alternatively spliced C9ORF72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms. Our findings indicate that repeat expansion in C9ORF72 is a major cause of both FTD and ALS.
doi:10.1016/j.neuron.2011.09.011
PMCID: PMC3202986  PMID: 21944778
7.  Mutations in the colony stimulating factor 1 receptor (CSF1R) cause hereditary diffuse leukoencephalopathy with spheroids 
Nature Genetics  2011;44(2):200-205.
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominantly inherited central nervous system white matter disease with variable clinical presentations including personality and behavioral changes, dementia, depression, parkinsonism, seizures, and others1,2. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor receptor 1 (encoded by CSF1R) in 14 families affected by HDLS. In one kindred, the de novo occurrence of the mutation was confirmed. Follow-up sequencing analyses identified an additional CSF1R mutation in a patient clinically diagnosed with corticobasal syndrome (CBS). In vitro, CSF-1 stimulation resulted in the rapid autophosphorylation of selected tyrosine-residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from a partial loss of CSF1R function. Since CSF1R is a critical mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.
doi:10.1038/ng.1027
PMCID: PMC3267847  PMID: 22197934
8.  Progranulin axis and recent developments in frontotemporal lobar degeneration 
Frontotemporal lobar degeneration (FTLD) is a devastating neurodegenerative disease that is the second most common form of dementia affecting individuals under age 65. The most common pathological subtype, FTLD with transactive response DNA-binding protein with a molecular weight of 43 kDa inclusions (FTLD-TDP), is often caused by autosomal dominant mutations in the progranulin gene (GRN) encoding the progranulin protein (PGRN). GRN pathogenic mutations result in haploinsufficiency, usually by nonsense-mediated decay of the mRNA. Since the discovery of these mutations in 2006, several groups have published data and animal models that provide further insight into the genetic and functional relevance of PGRN in the context of FTLD-TDP. These studies were critical in initiating our understanding of the role of PGRN in neural development, degeneration, synaptic transmission, cell signaling, and behavior. Furthermore, recent publications have now identified the receptors for PGRN, which will hopefully lead to additional therapeutic targets. Additionally, drug screens have been conducted to identify pharmacological regulators of PGRN levels to be used as potential treatments for PGRN haploinsufficiency. Here we review recent literature describing relevant data on GRN genetics, cell culture experiments describing the potential role and regulators of PGRN in the central nervous system, animal models of PGRN deficiency, and potential PGRN-related FTLD therapies that are currently underway. The present review aims to underscore the necessity of further elucidation of PGRN biology in FTLD-related neurodegeneration.
doi:10.1186/alzrt102
PMCID: PMC3372369  PMID: 22277331
9.  HUMAN GENETICS AS A TOOL TO IDENTIFY PROGRANULIN REGULATORS 
Journal of Molecular Neuroscience  2011;45(3):532-537.
Frontotemporal lobar degeneration (FTLD) is a common neurodegenerative disorder that predominantly affects individuals under the age of 65. It is known that the most common pathological subtype is FTLD with TAR DNA-binding protein 43 inclusions (FTLD-TDP). FTLD has a strong genetic component with about 50% of cases having a positive family history. Mutations identified in the progranulin gene (GRN) have been shown to cause FTLD-TDP as a result of progranulin haploinsufficiency. These findings suggest a progranulin-dependent mechanism in this pathological FTLD subtype. Thus, identifying regulators of progranulin levels is essential for new therapies and treatments for FTLD and related disorders. In this review, we discuss the role of genetic studies in identifying progranulin regulators, beginning with the discovery of pathogenic GRN mutations and additional GRN risk variants. We also cover more recent genetic advances, including the detection of variants in the transmembrane protein 106 B gene that increase FTLD-TDP risk presumably by modulating progranulin levels and the identification of a potential progranulin receptor, sortilin. This review highlights the importance of genetic studies in the context of FTLD and further emphasizes the need for future genetic and cell biology research to continue the effort in finding a cure for progranulin-related diseases.
doi:10.1007/s12031-011-9554-y
PMCID: PMC3310391  PMID: 21626010
progranulin; genetics; FTLD; TDP-43; TMEM106B; sortilin
10.  β-Amyloid Carrying the Dutch Mutation Has Diverse Effects on Calpain-Mediated Toxicity in Hippocampal Neurons 
Molecular Medicine  2011;18(1):178-185.
Hereditary cerebral hemorrhage with amyloidosis–Dutch type is a disorder associated with a missense mutation (E693Q) in the β-amyloid (Aβ)-coding region of the amyloid precursor protein (APP). This familial disease is characterized by cognitive deficits secondary to intracerebral hemorrhage and, in some cases, progressive Alzheimer’s disease (AD)-like dementia. Although this mutation was the first ever reported in the human APP gene, little is known about the molecular mechanisms underlying the direct toxic effects of this mutated Aβ on central neurons. In the present study, we assessed the role of calpain-mediated toxicity in such effects using an AD primary culture model system. Our results showed that Dutch mutant Aβ (E22Q) induced calpain-mediated cleavage of dynamin 1 and a significant decrease in synaptic contacts in mature hippocampal cultures. These synaptic deficits were similar to those induced by wild-type (WT) Aβ. In contrast, calpain-mediated tau cleavage leading to the generation of a 17-kDa neurotoxic fragment, as well as neuronal death, were significantly reduced in E22Q Aβ–treated neurons when compared with WT Aβ–treated ones. This complex regulation of the calpain-mediated toxicity pathway by E22Q Aβ could have some bearing in the pathobiology of this familial AD form.
doi:10.2119/molmed.2011.00366
PMCID: PMC3320137  PMID: 22160219
11.  INCREASED MEMBRANE CHOLESTEROL MIGHT RENDER MATURE HIPPOCAMPAL NEURONS MORE SUSCEPTIBLE TO BETA-AMYLOID-INDUCED CALPAIN ACTIVATION AND TAU TOXICITY 
A growing body of evidence suggests that beta-amyloid (Aβ), the main component of senile plaques, induces abnormal posttranslational processing of the microtubule-associated protein tau. We have recently described that, in addition to increasing tau phosphorylation, Aβ enhanced calpain activity leading to the generation of a toxic 17 kDa tau fragment in cultured hippocampal neurons. How aging, the greatest AD risk factor, might regulate this proteolytic event remains unknown. In this study, we assessed the susceptibility of cultured hippocampal neurons to Aβ-dependent 17 kDa tau production at different developmental stages. Our results revealed that mature neurons were more susceptible to Aβ-induced calpain activation leading to the generation of this fragment than young neurons. In addition, the production of this fragment correlated with a decrease in cell viability in mature hippocampal neurons. Secondly, we determined whether membrane cholesterol, a suspect player in AD, might mediate these age-dependent differences in Aβ-induced calpain activation. Filipin staining and an Amplex Red cholesterol assay showed that mature neuron membrane cholesterol levels were significantly higher than those detected in young ones. Furthermore, decreasing membrane cholesterol in mature neurons reduced their susceptibility to Aβ-dependent calpain activation, 17 kDa tau production, and cell death whereas increasing membrane cholesterol in young neurons enhanced these Aβ-mediated cellular processes. Finally, fura-2 calcium imaging indicated that membrane cholesterol alterations might change the vulnerability of cells to Aβ insult by altering calcium influx. Together these data suggested a potential role of cholesterol in linking aging to Aβ-induced tau proteolysis in the context of AD.
doi:10.1523/JNEUROSCI.0862-09.2009
PMCID: PMC2705291  PMID: 19357288
Alzheimer’s disease; amyloid; tau; calpain; membrane; cholesterol

Results 1-11 (11)