Frontotemporal dementia (FTD) is the most common form of early-onset dementia. Loss of neurons in the frontal and temporal lobes in the brain leads to progressive behavioral changes and language impairments in people affected by the disease. Most of the familial cases can be explained by a hexanucleotide (GGGGCC) repeat expansion in C9ORF72, a common feature shared between FTD and another degenerative disease, amyotrophic lateral sclerosis (ALS). Brain tissues from affected individuals show characteristic nuclear RNA foci containing the expanded repeat RNAs, as well as neuronal inclusions containing dipeptide repeat (DPR) proteins resulting from the translation of both sense and antisense repeat RNAs in all reading frames. Although reduced C9ORF72 protein function may contribute to disease, the more likely drivers of disease are mechanisms related to a gain of toxic function. Currently, intense efforts are being made to identify disease mechanisms amenable for the development of therapeutic strategies. The overall objective of this proposal is to evaluate the modulation of endogenous DPR protein levels within an appropriate physiological context by the potassium channel TASK1. Our hypothesis is that by decreasing DPR protein levels in human neurons it may be possible to restore a healthy control phenotype and delay aspects of disease pathogenesis and neurodegeneration. Our studies also aim to identify the mechanisms leading to TASK1-mediated clearance of DPR proteins in patient neurons, an aspect not yet understood. Altogether, our studies seek to reveal new therapeutic opportunities to treat C9ORF72-related FTD/ALS and possibly other neurodegenerative diseases associated with DPR proteins.