The <i>TMEM106B</i> rs1990621 protective variant is also associated with increased neuronal proportion

Li, Zeran; Farias, Fabiana; Dube, Umber; Del‐Aguila, Jorge L.; Mihindukulasuriya, Kathie A.; Fernández, María Victoria; Ibáñez, Laura; Budde, John; Wang, Fengxian; Lake, Allison M.; Deming, Yuetiva; Perez, James; Yang, Chengran; Bradley, Joseph; Davenport, Richard; Bergmann, Kristy; Benitez, Bruno A.; Dougherty, Joseph D.; Harari, Oscar; Cruchaga, Carlos

doi:10.1101/583286

Cited by 10 publications

(18 citation statements)

References 87 publications

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“…The TMEM106B locus has been implicated in cognitive aging, with functional consequences in frontotemporal dementia related to lysosomal activity [21][22][23]. A recent transcriptome study implicated protective TMEM106B variants in differences in neuronal proportions across LOAD patients, supporting the idea that impaired lysosomal function may lead to a toxic buildup of waste in the cell, a common process among many neurodegenerative disorders [42]. Therefore, the presence of TMEM106B variants in combination with other risk factors might alter the course and severity of neurodegeneration PLOS GENETICS across patient subtypes.…”

Section: Discussionmentioning

confidence: 93%

Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology

et al. 2020

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Late-Onset Alzheimer's disease (LOAD) is a common, complex genetic disorder wellknown for its heterogeneous pathology. The genetic heterogeneity underlying common, complex diseases poses a major challenge for targeted therapies and the identification of novel disease-associated variants. Case-control approaches are often limited to examining a specific outcome in a group of heterogenous patients with different clinical characteristics. Here, we developed a novel approach to define relevant transcriptomic endophenotypes and stratify decedents based on molecular profiles in three independent human LOAD cohorts. By integrating post-mortem brain gene co-expression data from 2114 human samples with LOAD, we developed a novel quantitative, composite phenotype that can better account for the heterogeneity in genetic architecture underlying the disease. We used iterative weighted gene co-expression network analysis (WGCNA) to reduce data dimensionality and to isolate gene sets that are highly co-expressed within disease subtypes and represent specific molecular pathways. We then performed single variant association testing using whole genome-sequencing data for the novel composite phenotype in order to identify genetic loci that contribute to disease heterogeneity. Distinct LOAD subtypes were identified for all three study cohorts (two in ROSMAP, three in Mayo Clinic, and two in Mount Sinai Brain Bank). Single variant association analysis identified a genome-wide significant variant in TMEM106B (p-value < 5×10 −8 , rs1990620 G) in the ROSMAP cohort that confers protection from the inflammatory LOAD subtype. Taken together, our novel approach can be used to stratify LOAD into distinct molecular subtypes based on affected disease pathways.

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Section: Discussionmentioning

confidence: 93%

Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology

et al. 2020

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“…However, contradictory findings make it difficult to understand how TMEM106B and PGRN functionally interact to increase the risk for FTLD-TDP. There is some evidence that the risk haplotype enhances inflammatory gene expression (Rhinn & Abeliovich, 2017;Ren et al, 2018), whereas the protective variant provides neuroprotection (Li et al, 2020). Functionally, TMEM106B is linked to the lysosomal protein degradation pathway and autophagy suggesting an interaction with similar functions of PGRN.…”

Section: Introductionmentioning

confidence: 99%

Loss of TMEM 106B potentiates lysosomal and FTLD ‐like pathology in progranulin‐deficient mice

et al. 2020

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Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss of function of TMEM106B is responsible for the increased disease risk of patients with GRN haploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, and TDP-43 pathology in single and double knockout animals. Grn À/À /Tmem106b À/À mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn À/À knockouts only occasionally show TDP-43 pathology, the double knockout mice exhibit deposition of phosphorylated TDP-43. Thus, a loss of function of TMEM106B may enhance the risk for GRN-associated FTLD by reduced protein turnover in the lysosomal/autophagic system.

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“…Notably, the same TMEM106B haplotype has been shown to modify disease risk or presentation in other neurodegenerative diseases, such as Alzheimer's disease and hippocampal sclerosis (Rutherford et al, 2012;Murray et al, 2014). In addition, TMEM106B haplotypes have also been associated with healthy aging (Rhinn & Abeliovich, 2017;Ren et al, 2018;Li et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin‐deficient mice

et al. 2020

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Progranulin (PGRN) and transmembrane protein 106B (TMEM 106B) are important lysosomal proteins implicated in frontotemporal lobar degeneration (FTLD) and other neurodegenerative disorders. Loss-of-function mutations in progranulin (GRN) are a common cause of FTLD, while TMEM106B variants have been shown to act as disease modifiers in FTLD. Overexpression of TMEM106B leads to lysosomal dysfunction, while loss of Tmem106b ameliorates lysosomal and FTLD-related pathologies in young Grn À/À mice, suggesting that lowering TMEM106B might be an attractive strategy for therapeutic treatment of FTLD-GRN. Here, we generate and characterize older Tmem106b À/À Grn À/À double knockout mice, which unexpectedly show severe motor deficits and spinal cord motor neuron and myelin loss, leading to paralysis and premature death at 11-12 months. Compared to Grn À/À , Tmem106b À/À Grn À/À mice have exacerbated FTLD-related pathologies, including microgliosis, astrogliosis, ubiquitin, and phospho-Tdp43 inclusions, as well as worsening of lysosomal and autophagic deficits. Our findings confirm a functional interaction between Tmem106b and Pgrn and underscore the need to rethink whether modulating TMEM106B levels is a viable therapeutic strategy.

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The TMEM106B rs1990621 protective variant is also associated with increased neuronal proportion

Cited by 10 publications

References 87 publications

Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology

Transcriptomic stratification of late-onset Alzheimer's cases reveals novel genetic modifiers of disease pathology

Loss of TMEM 106B potentiates lysosomal and FTLD ‐like pathology in progranulin‐deficient mice

Loss of Tmem106b exacerbates FTLD pathologies and causes motor deficits in progranulin‐deficient mice

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