Exploring TMEM106B in Neurodegeneration: Protein Interaction and Fibril-induced Neurotoxicity

PROJECT SUMMARY The increasing aging population presents a heightened risk of neurodegenerative diseases. Frontotemporal dementia (FTD) is one of these disorders and is the most common dementia in those under 60, results from genetic mutations, particularly GGGGCC(G4C2) hexanucleotide repeat expansions in the

C9orf72 gene. These mutations, normally occurring 2-30 times in healthy individuals, can extend to hundreds or thousands in C9orf72-related FTD and Amyotrophic Lateral Sclerosis (ALS) patients. TMEM106B is another gene that is linked with neurodegeneration and particularly FTD and codes for a transmembrane protein

localized to the lysosome. Genome Wide Association Studies have shown single nucleotide polymorphisms (SNPs) within the TMEM106B gene confer risk for various neurodegenerative disorders. It has been shown that TMEM106B asks as a genetic modifier for C9orf72-related FTD. This dissertation proposal delves into the complex interaction between TMEM106B and C9orf72 by examining the interplay between

TMEM106B and GA, a dipeptide repeat (DPR) proteins produced by C9orf72 hexanucleotide repeat expansions. My preliminary data shows increased C-terminal cleavage of TMEM106B when co-expressed with GA. Thus, I hypothesize that GA interacts with TMEM106B through its perturbation of the proteosome pathway which in turn perturbs the clearance of a TMEM106B C-terminal cleaved product

and subsequently leads to neurotoxicity. This proposal also intends to investigate the toxicity of TMEM106B aggregate prone fibrils. These fibrils were found in patients with different neurodegenerative disorder as well as aged individuals while absent in young disordered and control individuals. Individuals with risk SNPs have higher burden of TMEM106B fibrils which suggests a central

role in aging and neurodegeneration. Preliminary data shows that TMEM106B overexpression leads to neurotoxicity as well as subsequent mislocalization of nuclear RNA binding proteins (RBPs). Thus, I will test the hypothesis that TMEM106B fibrils play an important role in neurodegeneration and contribute to toxicity and disease pathogenesis through disruption of the NCT. The Specific Aims of

this project are to: 1) Determine the interaction of TMEM106B and C9orf72 repeat expansion; and 2) Determine the toxicity of TMEM106B fibrils and the underlying molecular mechanisms. Successful completion of the proposed Aims will provide insights into TMEM106B’s interaction with C9orf72 and TMEM106B fibril’s contribution to aging and disease.