Autophagy Functions Of Genes Mutated In ALS And Parkinson’s Disease

Abstract

TANK-binding kinase 1 (TBK1) phosphorylates Optineurin and mutations in either the kinase or the substrate can lead to ALS. Similarly, Pink1 phosphorylates Parkin and loss of function mutations in either can lead to Parkinson’s disease. Interestingly, all four proteins play roles in autophagy and mitophagy. PINK1 accumulates on the outer membrane of damaged mitochondria where it phosphorylates, in addition to Parkin, ubiquitin chains occurring on the outer mitochondrial membrane. These Phospho-S65 Ubiquitin chains bind to cytosolic Parkin and activate Parkin’s E3 ubiquitin ligase activity. This builds more chains on the mitochondrial surface for PINK1 to phosphorylate yielding a feedback amplification loop the drives mitophagy to completion. How ubiquitin chains or phospho-ubiquitin chains induce autophagy remains less clear. We have knocked out in HeLa cells a series of autophagy receptors including p62, NBR1, NDP52, Tax1BP1 and Optineurin revealing a hierarchy of autophagy receptors involved in mitophagy and revealing a link between them and those known to be involved in xenophagy. Interestingly, PINK1 accumulation on mitochondria alone, in the absence of Parkin, can recruit Optineurin to mitochondria and trigger mitophagy. Furthermore, in contrast to the central idea that autophagy receptors such as Optineurin bind LC3 to recruit cargo into autophagosomes, Optineurin following TBK1 phosphorylation can recruit Ulk1, DFCP1 and WIPI1 to mitochondria independently of LC3 proteins. Ubiquitin chains on mitochondrial can also activate Rab7 to promote pre-autophagosome enlargement and mitochondrial engulfment. New aspects regarding mitophagy in neurons will be presented.