Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis

Vass, Ryan; Ashbridge, Emily; Geser, Felix; Hu, William T.; Grossman, Murray; Clay-Falcone, Dana; Elman, Lauren; McCluskey, Leo; Lee, Virginia M.‐Y.; Deerlin, Vivianna M. Van; Trojanowski, John Q.; Chen‐Plotkin, Alice S.

doi:10.1007/s00401-010-0782-y

Cited by 110 publications

(104 citation statements)

References 30 publications

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“…106,109 ATXN2 expansions are a risk factor for ALS but not for FTD, 90 whereas the TMEM106B risk allele is a risk factor for FTD but not for ALS. 110 Phenotypic variability across the ALS-FTD spectrum (and probably other spectra) is, thus, believed to be largely due to various genetic polymorphisms with different cytotoxic or cytoprotective effects according to neuronal cell type. Better knowledge of these factors, whether they be environmental or genetic in nature, is important, as they could be targets for intervention, even in patients in whom the cause of the disease is unknown.…”

Section: From Biology To Therapymentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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| Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3-5 years after onset-a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

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Section: From Biology To Therapymentioning

confidence: 99%

The phenotypic variability of amyotrophic lateral sclerosis

2014

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“…Although the risk for FTLD-TDP conferred by TMEM106B risk alleles is strongest in those with progranulin mutations, it has recently been shown to play a role in the pathogenesis of FTLD-TDP caused by C9ORF72 repeat expansions (20,21) but not in other classes of FTLD, such as those caused by microtubule associated protein tau, MAPT mutations. Finally, the TMEM106B risk allele is associated with cognitive impairment in amyotrophic lateral sclerosis and is associated with the pathological presentation of Alzheimer's disease (22)(23)(24).…”

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confidence: 99%

Regulated Intramembrane Proteolysis of the Frontotemporal Lobar Degeneration Risk Factor, TMEM106B, by Signal Peptide Peptidase-like 2a (SPPL2a)

Brady

Zhou

2014

Journal of Biological Chemistry

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Background: TMEM106B polymorphisms are associated with some forms of dementia. Results: A pathway for the sequential processing of TMEM106B on the lysosome membrane has been identified. Conclusion: TMEM106B undergoes processing via removal of its lumenal domain, followed by intramembrane cleavage by the protease SPPL2a. Significance: This may represent a mechanism for regulation of TMEM106B levels.

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“…The risk association is more prominent in FTLD-TDP cases with GRN and C9ORF72 mutations (11,(13)(14)(15)(16)(17). The risk rs1990622 genotype has also been shown to be associated with cognitive impairment in ALS (18).…”

Section: Frontotemporal Lobar Degeneration (Ftld)mentioning

confidence: 94%

The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death

Suzuki¹,

Matsuoka

2016

Journal of Biological Chemistry

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A common genetic variation in the transmembrane protein 106B (TMEM106B) gene has been suggested to be a risk factor for frontotemporal lobar degeneration (FTLD) with inclusions of transactive response DNA-binding protein-43 (TDP-43) (FTLD-TDP), the most common pathological subtype in FTLD. Furthermore, previous studies have shown that TMEM106B levels are up-regulated in the brains of FTLD-TDP patients, although the significance of this finding remains unknown. In this study, we show that the overexpression of TMEM106B and its N-terminal fragments induces cell death, enhances oxidative stress-induced cytotoxicity, and causes the cleavage of TDP-43, which represents TDP-43 pathology, using cell-based models. TMEM106B-induced death is mediated by the caspase-dependent mitochondrial cell death pathways and possibly by the lysosomal cell death pathway. These findings suggest that the upregulation of TMEM106B may increase the risk of FTLD by directly causing neurotoxicity and a pathological phenotype linked to FTLD-TDP. Frontotemporal lobar degeneration (FTLD)2 is the second leading cause of presenile dementia, typically with an onset of disease before 65 years of age (1, 2). It is pathologically characterized by degeneration of the frontal and anterior temporal lobes of the cerebral cortices. Clinical characteristics include changes in personality and behavior and difficulties with language. Approximately 25-50% of FTLD cases are genetically inherited, and several genes, such as GRN (the gene encoding progranulin), MAPT, VCP, CHAMP2B, TARDBP, FUS, and C9ORF72, have been identified as FTLD-causative genes (3). FTLD has been recently recognized as a disease that has a common pathogenetic background with amyotrophic lateral sclerosis (ALS) (4). ALS is an incurable motor neuron degenerative disease, characterized by loss of both upper and lower motor neurons (5, 6). Approximately 15% of FTLD patients develop motor neuron disease, and more than 15% of ALS patients have cognitive and behavioral impairments (4, 7). Mutations in several genes, such as TARDBP and C9ORF72, lead to the development of both FTLD and ALS (1, 4, 8). An important pathological hallmark of FTLD and ALS is a cytoplasmic transactive response DNA-binding protein-43 (TDP-43) inclusion. TDP-43 is the major component of inclusions in ϳ50% of FTLD patients (subtype FTLD-TDP) and the majority of ALS patients (9, 10). However, currently, the pathogenetic mechanisms underlying these neurodegenerative diseases are not fully understood.A genome-wide association study and cohort studies have identified three SNPs (rs1990622, rs6966915, and rs1020004) in the transmembrane protein 106B (TMEM106B) gene region as genetic risk modifiers for FTLD-TDP (11-14). The risk association is more prominent in FTLD-TDP cases with GRN and C9ORF72 mutations (11,(13)(14)(15)(16)(17). The risk rs1990622 genotype has also been shown to be associated with cognitive impairment in ALS (18).TMEM106B is a glycosylated type 2 transmembrane protein, located in late endosomes and lysosomes, w...

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Risk genotypes at TMEM106B are associated with cognitive impairment in amyotrophic lateral sclerosis

Cited by 110 publications

References 30 publications

The phenotypic variability of amyotrophic lateral sclerosis

The phenotypic variability of amyotrophic lateral sclerosis

Regulated Intramembrane Proteolysis of the Frontotemporal Lobar Degeneration Risk Factor, TMEM106B, by Signal Peptide Peptidase-like 2a (SPPL2a)

The Lysosomal Trafficking Transmembrane Protein 106B Is Linked to Cell Death

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