Regulation of lysosomal potassium channels

University Of Pennsylvania, Philadelphia PA

Investigators

Linked publications, trials & patents

Abstract

Program Director/Principal Investigator (Last, First, Middle): Ren, Dejian The major goal of the proposed research is to understand how the ion channel TMEM175 we discovered controls lysosomal function and regulates neurodegenerative diseases. Lysosomes are uniquely important for many functions such as material digestion, recycling, cellular clearance, exocytosis, wound repair, Ca2+ signaling, nutrient sensing. They are also the platform for signaling networks involving the mTOR and AKT kinases and transcription factor TFEB. Lysosomal dysfunctions are implicated in numerous diseases such as lysosomal storage and neural degenerative diseases, and is a hallmark of aging. Despite the importance, their biophysical properties have been poorly defined, and there are several “controversies” even in processes as basic as acidification. We have recently started to fill the knowledge gap by using organelle electrophysiology, channel protein discovery and functional studies in mice and human. In the past period, we have focused on the TMEM175 protein that we discovered to form the K+ channel we first recorded. TMEM175 is a major locus linked to several neurodegenerative diseases including Parkinson's disease (PD) and Lewy body dementia. We found that TMEM175 is important for the acidification of lysosomes. TMEM175 knockout (KO) neurons are prone to stress-induced damages and have accelerated spreading of misfolded α-synuclein. KO mice lose dopaminergic neurons, a hallmark of PD. We also found that a PD-associated variations affect lysosomal ion channel function and modulate Parkinson's disease pathology. Thus, TMEM175 is important for lysosomal function and neuronal fitness, and bidirectionally regulates neurodegenerative diseases. We propose to further reveal how TMEM175 is activated by the kinase protein AKT (Aim 1), how the channel contributes to lysosomal function such as acidification (Aim 2) and how its genetic variations contribute to variations in neuronal function and neurological diseases (Aim 2). As TMEM175 is implicated in PD and several other neurodegenerative diseases, the work will also reveal how genetic variations contribute to functional variations of lysosomes and neuronal fitness, and will provide foundation for the intervention of neural degeneration diseases. Page