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1.  TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson’s disease 
Background
A rare variant in the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) gene has been reported to be a genetic risk factor for Alzheimer’s disease by two independent groups (Odds ratio between 2.9-4.5). Given the key role of TREM2 in the effective phagocytosis of apoptotic neuronal cells by microglia, we hypothesized that dysfunction of TREM2 may play a more generalized role in neurodegeneration. With this in mind we set out to assess the genetic association of the Alzheimer’s disease-related risk variant in TREM2 (rs75932628, p.R47H) with other related neurodegenerative disorders.
Results
The study included 609 patients with frontotemporal dementia, 765 with amyotrophic lateral sclerosis, 1493 with Parkinson’s disease, 772 with progressive supranuclear palsy, 448 with ischemic stroke and 1957 controls subjects free of neurodegenerative disease. A significant association was observed for the TREM2 p.R47H substitution in susceptibility to frontotemporal dementia (OR = 5.06; p-value = 0.001) and Parkinson’s disease (OR = 2.67; p-value = 0.026), while no evidence of association with risk of amyotrophic lateral sclerosis, progressive supranuclear palsy or ischemic stroke was observed.
Conclusions
Our results suggest that the TREM2 p.R47H substitution is a risk factor for frontotemporal dementia and Parkinson’s disease in addition to Alzheimer’s disease. These findings suggest a more general role for TREM2 dysfunction in neurodegeneration, which could be related to its role in the immune response.
doi:10.1186/1750-1326-8-19
PMCID: PMC3691612  PMID: 23800361
TREM2; Frontotemporal dementia; Parkinson disease; Genetic association
2.  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
3.  Ataxin-2 repeat-length variation and neurodegeneration 
Human Molecular Genetics  2011;20(16):3207-3212.
Expanded glutamine repeats of the ataxin-2 (ATXN2) protein cause spinocerebellar ataxia type 2 (SCA2), a rare neurodegenerative disorder. More recent studies have suggested that expanded ATXN2 repeats are a genetic risk factor for amyotrophic lateral sclerosis (ALS) via an RNA-dependent interaction with TDP-43. Given the phenotypic diversity observed in SCA2 patients, we set out to determine the polymorphic nature of the ATXN2 repeat length across a spectrum of neurodegenerative disorders. In this study, we genotyped the ATXN2 repeat in 3919 neurodegenerative disease patients and 4877 healthy controls and performed logistic regression analysis to determine the association of repeat length with the risk of disease. We confirmed the presence of a significantly higher number of expanded ATXN2 repeat carriers in ALS patients compared with healthy controls (OR = 5.57; P= 0.001; repeat length >30 units). Furthermore, we observed significant association of expanded ATXN2 repeats with the development of progressive supranuclear palsy (OR = 5.83; P= 0.004; repeat length >30 units). Although expanded repeat carriers were also identified in frontotemporal lobar degeneration, Alzheimer's and Parkinson's disease patients, these were not significantly more frequent than in controls. Of note, our study identified a number of healthy control individuals who harbor expanded repeat alleles (31–33 units), which suggests caution should be taken when attributing specific disease phenotypes to these repeat lengths. In conclusion, our findings confirm the role of ATXN2 as an important risk factor for ALS and support the hypothesis that expanded ATXN2 repeats may predispose to other neurodegenerative diseases, including progressive supranuclear palsy.
doi:10.1093/hmg/ddr227
PMCID: PMC3140823  PMID: 21610160
4.  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
5.  Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathology caused by progranulin mutations 
BMC Genomics  2011;12:527.
Background
Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative disorder that can be triggered through genetic or sporadic mechanisms. MicroRNAs (miRNAs) have become a major therapeutic focus as their pervasive expression and powerful regulatory roles in disease pathogenesis become increasingly apparent. Here we examine the role of miRNAs in FTLD patients with TAR DNA-binding protein 43 pathology (FTLD-TDP) caused by genetic mutations in the progranulin (PGRN) gene.
Results
Using miRNA array profiling, we identified the 20 miRNAs that showed greatest evidence (unadjusted P < 0.05) of dysregulation in frontal cortex of eight FTLD-TDP patients carrying PGRN mutations when compared to 32 FTLD-TDP patients with no apparent genetic abnormalities. Quantitative real-time PCR (qRT-PCR) analyses provided technical validation of the differential expression for 9 of the 20 miRNAs in frontal cortex. Additional qRT-PCR analyses showed that 5 out of 9 miRNAs (miR-922, miR-516a-3p, miR-571, miR-548b-5p, and miR-548c-5p) were also significantly dysregulated (unadjusted P < 0.05) in cerebellar tissue samples of PGRN mutation carriers, consistent with a systemic reduction in PGRN levels. We developed a list of gene targets for the 5 candidate miRNAs and found 18 genes dysregulated in a reported FTLD mRNA study to exhibit anti-correlated miRNA-mRNA patterns in affected cortex and cerebellar tissue. Among the targets is brain-specific angiogenesis inhibitor 3, which was recently identified as an important player in synapse biology.
Conclusions
Our study suggests that miRNAs may contribute to the pathogenesis of FTLD-TDP caused by PGRN mutations and provides new insight into potential future therapeutic options.
doi:10.1186/1471-2164-12-527
PMCID: PMC3229715  PMID: 22032330
Frontotemporal lobar degeneration; TDP-43; microRNA; progranulin
6.  Prominent Phenotypic Variability Associated with Mutations in Progranulin 
Neurobiology of aging  2007;30(5):739-751.
Mutations in progranulin (PGRN) are associated with frontotemporal dementia with or without parkinsonism. We describe the prominent phenotypic variability within and among eight kindreds evaluated at Mayo Clinic Rochester and/or Mayo Clinic Jacksonville in whom mutations in PGRN were found. All available clinical, genetic, neuroimaging and neuropathologic data was reviewed. Age of onset ranged from 49 to 88 years and disease duration ranged from 1 to 14 years. Clinical diagnoses included frontotemporal dementia (FTD), primary progressive aphasia, FTD with parkinsonism, parkinsonism, corticobasal syndrome, Alzheimer’s disease, amnestic mild cognitive impairment, and others. One kindred exhibited maximal right cerebral hemispheric atrophy in all four affected individuals, while another had maximal left hemisphere involvement in all three of the affected. Neuropathologic examination of 13 subjects revealed frontotemporal lobar degeneration with ubiquitin-positive inclusions plus neuronal intranuclear inclusions in all cases. Age of onset, clinical phenotypes and MRI findings associated with most PGRN mutations varied significantly both within and among kindreds. Some kindreds with PGRN mutations exhibited lateralized topography of degeneration across all affected individuals.
doi:10.1016/j.neurobiolaging.2007.08.022
PMCID: PMC3164546  PMID: 17949857
Frontotemporal dementia; FTDP-17; Progranulin; PGRN; MRI
7.  Alzheimer's Disease-Like Phenotype Associated With the c.154delA Mutation in Progranulin 
Archives of neurology  2010;67(2):171-177.
Objective
To characterize a kindred with a familial neurodegenerative disorder associated with a mutation in progranulin (PGRN), emphasizing the unique clinical features in this kindred.
Design
Clinical, radiologic, pathologic, and genetic characterization of a kindred with a familial neurodegenerative disorder.
Setting
Multispecialty group academic medical center.
Patients
Affected members of a kindred with dementia +/- parkinsonism associated with a unique mutation in PGRN.
Main Outcome Measure
Genotype-phenotype correlation.
Results
Ten affected individuals were identified, among whom six presented with initial amnestic complaints resulting in initial diagnoses of AD or amnestic mild cognitive impairment (MCI). A minority of individuals presented with features characteristic of FTD. The ages of onset of generation II (mean 75.8 years, range 69-80 years) were far greater than those of generation III (mean 60.7 years, range 55-66 years). The pattern of cerebral atrophy varied widely among affected individuals. Neuropathology in six individuals showed frontotemporal lobar degeneration with ubiquitin positive neuronal cytoplasmic and intranuclear inclusions (FTLD-U + NII). PGRN analysis revealed a single base pair deletion in exon 2 (c.154delA), causing a frameshift (p.Thr52Hisfs×2) and therefore creation of a premature termination codon and likely null allele.
Conclusions
We describe a large kindred in which the majority of affected individuals had clinical presentations resembling AD or amnestic MCI in association with a mutation in PGRN and underlying FTLD-U + NII neuropathology. This is in distinct contrast to previously reported kindreds, where clinical presentations have typically been within the spectrum of FTLD. The basis for the large difference in age of onset between generations will require further study.
doi:10.1001/archneurol.2010.113
PMCID: PMC2902004  PMID: 20142525
MRI; progranulin; frontotemporal dementia; PGRN
8.  Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members 
Brain  2009;132(3):583-591.
Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53–94 ng/ml) and 191 non-GRN mutation carriers (range: 115–386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The ∼75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.
doi:10.1093/brain/awn352
PMCID: PMC2664450  PMID: 19158106
Progranulin; ELISA; frontotemporal lobar degeneration; Alzheimer's disease
9.  Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis 
PLoS Genetics  2008;4(9):e1000193.
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis.
Author Summary
The abnormal accumulation of disease proteins in neuronal cells of the brain is a characteristic feature of many neurodegenerative diseases. Rare mutations in the genes that encode the accumulating proteins have been identified in these disorders and are crucial for the development of cell and animal models used to study neurodegeneration. Recently, the TAR DNA-binding protein 43 (TDP-43) was identified as the disease accumulating protein in patients with frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). TDP-43 was also found in the brains of 20–30% of patients with Alzheimer's disease (AD). Here, we evaluated whether mutations in TDP-43 cause disease in a cohort of 296 patients presenting with FTLD, ALS or AD. We identified three missense mutations in three out of 92 familial ALS patients (3.3%), and no mutations in AD or FTLD patients. All the identified mutations clustered in exon 6, which codes for a highly conserved region in the C-terminal part of the TDP-43 protein, which is known to be involved in the interaction of TDP-43 with other proteins. We conclude that mutations in TDP-43 are a rare cause of familial ALS, but so far are not found in other neurodegenerative diseases.
doi:10.1371/journal.pgen.1000193
PMCID: PMC2527686  PMID: 18802454
10.  Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia 
Human Molecular Genetics  2008;17(23):3631-3642.
Loss-of-function mutations in progranulin (GRN) cause ubiquitin- and TAR DNA-binding protein 43 (TDP-43)-positive frontotemporal dementia (FTLD-U), a progressive neurodegenerative disease affecting ∼10% of early-onset dementia patients. Here we expand the role of GRN in FTLD-U and demonstrate that a common genetic variant (rs5848), located in the 3′-untranslated region (UTR) of GRN in a binding-site for miR-659, is a major susceptibility factor for FTLD-U. In a series of pathologically confirmed FTLD-U patients without GRN mutations, we show that carriers homozygous for the T-allele of rs5848 have a 3.2-fold increased risk to develop FTLD-U compared with homozygous C-allele carriers (95% CI: 1.50–6.73). We further demonstrate that miR-659 can regulate GRN expression in vitro, with miR-659 binding more efficiently to the high risk T-allele of rs5848 resulting in augmented translational inhibition of GRN. A significant reduction in GRN protein was observed in homozygous T-allele carriers in vivo, through biochemical and immunohistochemical methods, mimicking the effect of heterozygous loss-of-function GRN mutations. In support of these findings, the neuropathology of homozygous rs5848 T-allele carriers frequently resembled the pathological FTLD-U subtype of GRN mutation carriers. We suggest that the expression of GRN is regulated by miRNAs and that common genetic variability in a miRNA binding-site can significantly increase the risk for FTLD-U. Translational regulation by miRNAs may represent a common mechanism underlying complex neurodegenerative disorders.
doi:10.1093/hmg/ddn257
PMCID: PMC2581433  PMID: 18723524

Results 1-10 (10)