The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function

Brady, Owen A.; Zheng, Y.; Murphy, Kira; Huang, Marshall J.; Hu, Fenghua

doi:10.1093/hmg/dds475

Cited by 177 publications

(219 citation statements)

References 32 publications

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“…Similar results were also demonstrated in previous in vitro studies (19,20,22). Given that the degradation of progranulin occurs in lysosomes (30), the effect of the TMEM106B overexpression on the progranulin level in the current study may reflect the impairment of lysosomal function, caused by the overexpression of TMEM106B, as reported previously (19,20,24). In support of this idea, the treatment with the lysosomal protease inhibitor leupeptin increased progranulin levels (Fig.…”

Section: Tmem106b Toxicitysupporting

confidence: 92%

“…In agreement, very recently, Busch et al (32) found that increased expression of TMEM106B causes cytotoxicity that requires lysosome localization. Furthermore, some earlier studies showed that lysosomal function and morphology are impaired by TMEM106B overexpression (19,20,24). Collectively, these data suggest that the TMEM106B-induced cell death is at least partially mediated by lysosomal cell death (33).…”

Section: Tmem106b Toxicitymentioning

confidence: 61%

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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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Section: Tmem106b Toxicitysupporting

confidence: 92%

Section: Tmem106b Toxicitymentioning

confidence: 61%

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

Suzuki¹,

Matsuoka

2016

Journal of Biological Chemistry

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“…Rabbit anti-TMEM106B was generated against the ICD as described (18). Rabbit anti-TMEM106A antibodies were generated by Pocono Rabbit Farm & Laboratory using the recombinant Gst-TMEM106A ICD region (amino acids 1-66) purified from bacteria as the antigen.…”

Section: Methodsmentioning

confidence: 99%

“…The SNPs associated with increased risk for FTLD-TDP do not result in mutations in the TMEM106B protein but instead lead to elevated mRNA and protein levels of TMEM106B (14,17). Increased TMEM106B levels have been shown to cause various lysosomal defects including altered morphology, impaired acidification, and reduced degradative capacity (17,18). Furthermore, a coding variant T185S, in linkage disequilibrium with the protective allele of TMEM106B, has been proposed to be more rapidly degraded, further implicating elevated TMEM106B levels as a potential mechanism underlying FTLD risk (19).…”

mentioning

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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“…However, it is predicted to have transcriptional regulatory property based upon its structure. TMEM106B (transmembrane protein 106B) localizes to late endosomes and lysosomes, and its expression is inversely related to lysosomal activity (16,17). EPS15 (Epidermal growth factor receptor substrate 15) is a clathrin-coated pit adaptor protein (18,19).…”

Section: Analysis Of Protein Expression In Differentiated Monocytes-mentioning

confidence: 99%

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

Nicholas

Tang²,

Zhang

et al. 2015

Molecular & Cellular Proteomics

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The differentiation of monocytes into macrophages and dendritic cells involves mechanisms for activation of the innate immune system in response to inflammatory stimuli, such as pathogen infection and environmental cues. Epigenetic reprogramming is thought to play an important role during monocyte differentiation. Complementary to cell surface markers, the characterization of monocytic cell lineages by mass spectrometry based protein/histone expression profiling opens a new avenue for studying immune cell differentiation. Here, we report the application of mass spectrometry and bioinformatics to identify changes in human monocytes during their differentiation into macrophages and dendritic cells. Our data show that linker histone H1 proteins are significantly down-regulated during monocyte differentiation. Although highly enriched H3K9-methyl/S10-phos/K14-acetyl tri-modification forms of histone H3 were identified in monocytes and macrophages, they were dramatically reduced in dendritic cells. In contrast, histone H4 K16 acetylation was found to be markedly higher in dendritic cells than in monocytes and macrophages. We also found that global hyperacetylation generated by the nonspecific histone deacetylase HDAC inhibitor Apicidin induces monocyte differentiation. Together, our data suggest that specific regulation of inter-and intra-histone modifications including H3 K9 methylation, H3 S10 phosphorylation, H3 K14 acetylation, and H4 K16 acetylation must occur in concert with chromatin remodeling by linker histones for cell cycle progression and differentiation of human myeloid cells into macrophages and dendritic cells. Molecular & Cellular

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The frontotemporal lobar degeneration risk factor, TMEM106B, regulates lysosomal morphology and function

Cited by 177 publications

References 32 publications

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

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

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

Quantitative Proteomics Reveals a Role for Epigenetic Reprogramming During Human Monocyte Differentiation

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