TMEM106B risk converges on C-terminal fragment homeostasis: genetics, mechanisms and therapy.

TMEM106B is a genetic modifier influencing susceptibility to multiple neurodegenerative disorders, including frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), Alzheimer's disease, Parkinson's disease, and limbic-predominant age-related TDP-43 encephalopathy, as well as contributing to healthy brain aging and neuronal reserve. The gene harbours single nucleotide polymorphisms and structural variants that define risk and protective haplotypes, and despite extensive efforts to identify the functional variant within these haplotypes, consensus remains elusive. In this review, we synthesize current knowledge of TMEM106B genetics from human cohorts and mechanistic studies, highlighting how variants may influence its regulatory network and protein levels, with an emphasis on its aggregation-prone C-terminal domain. We further integrate evidence on the roles of TMEM106B within the endo-lysosomal system and beyond, including insights into protein structure, posttranslational modifications, interactors, proteolytic processing, and fibril formation. These findings are contextualized using data from mouse and induced pluripotent stem cell (iPSC) models, highlighting current gaps in the available models and the advances required to study its functions and cleavage. Finally, we explore therapeutic strategies targeting TMEM106B, focusing on modulation of expression, specific functional pathways, and fibril formation.