Thursday, April 3, 2025
4/3/2025
The Role of TMEM106B in FTLD-TDP Pathogenesis - PROJECT SUMMARY/ABSTRACT Alzheimer disease and related dementias (ADRD) comprise a group of neurodegenerative diseases characterized by progressive decline of cognitive, behavioral, and/or motor function. These conditions place a significant burden on patients, families, and the healthcare system. Among the ADRDs is frontotemporal dementia (FTD), with approximately half of FTD cases characterized pathologically by frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP). Single nucleotide polymorphisms (SNPs) in TMEM106B are known to alter risk of FTLD-TDP. TMEM106B is a protein localized to late endosomes and lysosomes and has been reported to play a role in endolysosomal trafficking and brain myelination. Only one TMEM106B SNP causes a coding change, altering the amino acid at position 185 from threonine to serine (T185S). The TT185 haplotype is associated with significantly increased risk of FTLD-TDP relative to SS185. The SNP is also in high linkage disequilibrium with other TMEM106B SNPs, marking the coding change as a potential mechanism behind TMEM106B’s modulation of disease risk. The coding SNP of TMEM106B has not been studied extensively, though the coding change has been reported to alter protein half-life and autophagic flux in the cell. Recently, four groups published the discovery of TMEM106B amyloid fibrils in sarkosyl-insoluble cortical lysates across a range of neurodegenerative diseases, including FTLD-TDP. In preliminary studies, we have observed that accumulation of TMEM106B fibrils is positively associated with the TT185 haplotype. We speculate that the TMEM106B risk haplotype drives fibril formation and endolysosomal dysfunction, both of which contribute to neuron loss in disease. The studies outlined in this proposal will characterize the biological consequences of TMEM106B fibril formation in the diseased human brain and investigate TMEM106B haplotype-specific differences in endolysosomal function in a new cell model system. In Aim 1, we will identify protein interactors of TMEM106B fibrils in postmortem FTLD-TDP and non-diseased brains to test the hypothesis that TMEM106B fibrils exhibit disease-specific interactions that drive neuron loss. In Aim 2, mechanistic studies will be performed in novel, isogenic iPSC-derived neuron models stably expressing TMEM106B coding variants to test the hypothesis that the TMEM106B risk haplotype impairs endolysosomal function. We will also assess mechanistic relationships between TMEM106B and top interactors identified in Aim 1, and how they may vary with TMEM106B haplotype. We anticipate that this work will help identify novel protein targets to investigate or target for therapeutic development.
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