Abstract
Frontotemporal lobar degeneration (FTLD) represents a heterogeneous group of neurodegenerative disorders that progressively disrupt core human characteristics. FTLD accounts for 10-20% of all young-onset dementias. The atrophy in frontotemporal brain regions is caused by abnormal accumulation of disease proteins, such as TDP-43. In 2010, variants in TMEM106B were identified as the first common genetic risk factor for FTLD and as the most important modifier of disease risk in patients with progranulin (GRN) mutations (FTLD-GRN). More recent studies also implicate TMEM106B in multiple brain disorders and aging as well as a disease modifier in cancer and Covid-19. The involvement of this lysosomal protein TMEM106B in this wide variety of diseases highlights the need to improve our understanding of TMEM106B biology and function. In this project, I will perform an in-depth characterization and explore the role of TMEM106B in vesicle trafficking (endo- and exocytosis) and extracellular vesicle biology. By modulating these pathways, variations in TMEM106B could mediate the spreading of disease proteins. In this context, I will investigate the role of TMEM106B in FTLD-GRN and study the underlying disease interaction between TMEM106B and GRN. Our findings will also have value beyond the scope of neurodegeneration by contributing to our basic understanding of TMEM106B and its role in the endolysosomal pathway and could potentially lead towards new therapeutic avenues.
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