Abstract
TMEM106B haplotypes have been identified as risk factors for several neurodegenerative diseases such as Frontotemporal Lobar Degeneration with TDP-43 aggregates (FTLD-TDP) and Alzheimer's Disease (AD) and healthy aging, suggesting that they determine neuronal vulnerability. These haplotypes regulate expression of TMEM106B, a lysosomal type-II transmembrane protein, being the risk haplotype causative of a slight expression increase. In this project I hypothesize that subtle changes in TMEM106B expression condition neuronal fitness by dysregulating lysosomal physiology. To study this, I will generate isogenic PSC-derived cortical neurons with different TMEM106B expression levels: a full knockout (TMEM106B-/-) and an inducible-reversible overexpression (TMEM106BOE) model. These will be transplanted in the brains of AppNL-G-F and Grn-/- mice as models of AD and FTLD-TDP, respectively, to analyze how a neurodegenerative environment affects neurons in a TMEM106B expression-dependent manner. Lastly, I also aim to perform an in depth characterization of the lysosomes in these neurons in vitro by analyzing their proteome, trafficking, activity, size and localization and validating these results in the transplanted brain slices. Overall, this project aims to shed light into the molecular mechanism through which TMEM106B expression regulates neuronal vulnerability to disease by integrating neuropathological outcomes observed in the transplanted neurons with lysosomal dysfunctions.
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