TMEM106b as a lysosomal adaptor to influence brain aging and tau pathogenesis

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Abstract TMEM106B first came to the attention of the neurodegeneration community as a modifier of disease risk in FTLD-TDP, where the protective haplotype was significantly less common in subjects than in healthy controls. Since this discovery, TMEM106B's protective influence has been extended to hippocampal sclerosis in aging, cognitive symptoms in ALS and PD, transcriptional indicators of brain aging, and functional resilience against neuropathological burden. Given its impact, we know surprisingly little about TMEM106B function. TMEM106B is localized to the late endosome and lysosome where past work suggests it regulates vesicle size and enzyme content, but has been much less definitive about its effect on lysosomal function. The protective TMEM106B haplotype is less transcriptionally active than the common (risk) variant and the only coding SNP identified appears to increase protein turnover, together suggesting that mild reduction of TMEM106B levels may be optimal for cognitive health. Based on past studies, we hypothesize that TMEM106B regulates lysosomal homeostasis through both local protein interactions at the lysosome and through nuclear signaling via TFEB. We further propose that this role becomes more critical with aging and disease, where lysosomal function must be maintained under cellular stress. As a platform for testing how TMEM106B levels or isoform impact lysosome composition and function in the healthy brain and under stress of aging or neuropathology, we have generated an allelic series of mice in which TMEM106B levels have been constitutively reduced, deleted, or substituted with a coding variant. In our first aim, we will test how TMEM106B levels affect lysosome pH, size, and catabolic function in the healthy brain and under conditions of aging and tauopathy. In our second aim, we will test whether TMEM106B influences lysosomal composition through local protein interactions, nuclear transcription, or both. In our final aim, we will test how the lone coding variant affects TMEM106B localization and lysosomal properties to determine whether this variant partially phenocopies TMEM106B loss of function. In each aim, we will leverage the technical capabilities of our Metabolomics and Proteomics Cores and the power of lysosomal immunoprecipitation to obtain an unbiased and up-close view of how lysosome composition and catabolism is influenced by TMEM106B. The role of TMEM106B has yet to be clarified and the existing literature is conflicted about its impact on the cell. But by tackling this protein in vivo under native expression conditions using the tools and technologies afforded by our Program, we have an unparalleled opportunity to conclusively determine how this protein influences lysosomal function in cells relevant to Alzheimer's disease and under conditions of aging and tauopathy that attend dementia. Ultimately, we hope that our work will offer mechanistic insight into the outsized influence held by this non-descript lysosomal protein across a growing swath of neurodegenerative conditions.