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

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.

Downregulation of ATP6V1A Involved in Alzheimer’s Disease via Synaptic Vesicle Cycle, Phagosome, and Oxidative Phosphorylation

“…Genomic studies in mice and flies have shown that knockout of ATPase caused impaired presynaptic transmission, along with alterations in the amount and morphology of synapses [ 41 , 42 ]. These were important processes of V-ATPase deficiency contributing to cognitive impairment and neuronal degeneration [ 7 ], consistent with our findings of the participation of low ATP6V1A-mediated synaptic vesicle cycle in AD pathogenesis.…”

“…This gradient of acidification is potentially mediated by vacuolar H + -ATPase (V-ATPase), a multisubunit enzyme consisting of V0 and V1 sectors that pumps protons into the lysosomal lumen by ATP consumption [ 6 ]. Dysfunction of V-ATPase-dependent acidification disrupts the trafficking of substrates between endolysosomal compartments, which may facilitate molecular steps for neuronal degeneration, such as AD [ 7 ].…”

The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour

“…Thus, our data provides further evidence for the importance of V-ATPase regulation for neurodevelopment. Moreover, our detection of cytosolic accumulation of potentially undegraded material in DEL neurons is consistent with similar examples of V-ATPase subunit disruption [ 59 , 60 ], supporting our findings that the absence of NCOA7 negatively affects lysosomal physiology. We did not, however, observe evidence for more overt lysosomal storage in primary neurons as has been described in other V-ATPase-associated mutant models [ 56 ].…”

Regulation of V-ATPase Activity and Organelle pH by Phosphatidylinositol Phosphate Lipids

“…Fig4-and Vac14-deficient mice show early neurodegeneration that has been attributed to defects in autophagy as well as the defective trafficking leading to vacuolation (Ferguson et al, 2009). Although complete loss of V-ATPase activity is lethal in mammals (Sun-Wada et al, 2000), compromised lysosomal acidification is associated with multiple neurodegenerative diseases and aging (Colacurcio and Nixon, 2016;Song et al, 2020). One form of Batten's disease arises from mutations in the CLN1 gene which compromise trafficking of the a1 subunit isoform and results in elevated lysosomal pH and severe neurodegeneration (Bagh et al, 2017).…”