The role of autophagic kinases in regulation of axonal function

Abstract

Autophagy is an essential process for maintaining cellular homeostasis. Highlighting the importance of proper functioning of autophagy in neurons, disruption of autophagy is a common finding in neurodegenerative diseases. In recent years, evidence has emerged for the role of autophagy in regulating critical axonal functions. In this review, we discuss kinase regulation of autophagy in neurons, and provide an overview of how autophagic kinases regulate axonal processes, including axonal transport and axonal degeneration and regeneration. We also examine mechanisms for disruption of this process leading to neurodegeneration, focusing on the role of TBK1 in pathogenesis of Amyotrophic Lateral Sclerosis.

Keywords: ALS; TBK1; ULK1; autophagy; axon; kinase; mTOR.

FIGURE 1

Role of autophagic kinases in regulating autophagy. (A) The autophagic kinase AMPK phosphorylates ULK1 to activate autophagy, while mTORC1 phosphorylates ULK1 to inhibit autophagy. ULK1 then phosphorylates Beclin-1 in the VPS34 complex to activate VPS34. VPS34 phosphorylates phosphatidylinositol to regulate the growing autophagosome membrane. The kinase LRRK2 phosphorylates Endophilin-A, which promotes the formation of autophagosome membranes. LRRK2 also phosphorylates Beclin-1 to inhibit the VSP34 complex. (B) TBK1 regulates initiation of autophagy via phosphorylation of several autophagic proteins. TBK1 phosphorylates SMCR8, which exists in a complex with WDR41 and C9orf72 and regulates autophagic flux. TBK1 phosphorylation of Rab7A targets damaged mitochondria to autophagosomal membranes. TBK1 also directly phosphorylates GABARAP and LC3, which prevents premature removal of GABARAP and LC3 from autophagosomal membranes. TBK1 enhances the targeting of ubiquinated proteins to the phagophore via phosphorylation of the adaptor proteins OPTN and p62. Created in BioRender.com.