The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases

• Type of Material: Article
• Authors: Qiaoyun Song, Emory University; Bo Meng, Emory University; Haidong Xu, Emory University; Zixu Mao, Emory University
• Language: English
• Date: 2020-05-11
• Publisher: BMC Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s). 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s40035-020-00196-0
• Title of Journal or Parent Work: Translational Neurodegeneration
• Volume: 9
• Issue: 1
• Start Page: 17
• End Page: 17
• Grant/Funding Information: This work was supported in part by grants R01NS107505 and R01NS095269 to Z.M.
• Keywords: Neurosciences & Neurology; Disulfide bond formation; Life Sciences & Biomedicine; Alpha sinuclein; Alzheimer's disease; Vacuolar-type ATPase; Yeast vacuolar; Autophagy; Neurosciences; Molecular cloning; H+-atpase; Proton pump; Lysosomal acidification; Accessory subunit; Science & Technology; Neurodegeneration; V-atpase
• Research Categories: Biology, Molecular; Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Background: Lysosomes digest extracellular material from the endocytic pathway and intracellular material from the autophagic pathway. This process is performed by the resident hydrolytic enzymes activated by the highly acidic pH within the lysosomal lumen. Lysosome pH gradients are mainly maintained by the vacuolar (H+) ATPase (or V-ATPase), which pumps protons into lysosomal lumen by consuming ATP. Dysfunction of V-ATPase affects lysosomal acidification, which disrupts the clearance of substrates and leads to many disorders, including neurodegenerative diseases. Main body: As a large multi-subunit complex, the V-ATPase is composed of an integral membrane V0 domain involved in proton translocation and a peripheral V1 domain catalyzing ATP hydrolysis. The canonical functions of V-ATPase rely on its H+-pumping ability in multiple vesicle organelles to regulate endocytic traffic, protein processing and degradation, synaptic vesicle loading, and coupled transport. The other non-canonical effects of the V-ATPase that are not readily attributable to its proton-pumping activity include membrane fusion, pH sensing, amino-acid-induced activation of mTORC1, and scaffolding for protein-protein interaction. In response to various stimuli, V-ATPase complex can reversibly dissociate into V1 and V0 domains and thus close ATP-dependent proton transport. Dysregulation of pH and lysosomal dysfunction have been linked to many human diseases, including neurodegenerative disorders such as Alzheimer disease, Parkinson's disease, amyotrophic lateral sclerosis as well as neurodegenerative lysosomal storage disorders. Conclusion: V-ATPase complex is a universal proton pump and plays an important role in lysosome acidification in all types of cells. Since V-ATPase dysfunction contributes to the pathogenesis of multiple neurodegenerative diseases, further understanding the mechanisms that regulate the canonical and non-canonical functions of V-ATPase will reveal molecular details of disease process and help assess V-ATPase or molecules related to its regulation as therapeutic targets.