Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Abstract

Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson Disease and Alzheimer Disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal proteolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.

Protein homeostasis of a metastable subproteome associated with Alzheimer’s disease

“…Hence, RAB6A, which is a central gene in the AD metastable network described in this work, could play an important role in the regulation of the metastable proteins by directing them toward the endosomallysosomal degradation machinery, thereby preventing their accumulation in the cytoplasm. Another two genes in the group that we found are ATP6V1H, which encodes a protein subunit of a vacuolar ATPase involved in clathrin-mediated endocytosis (57,58) and whose role in regulating lysosomal pH has been recently been linked to neurodegeneration (59), and ATL1, which is involved in ER trafficking (60,61). In fact, all 10 genes that we found to be related to trafficking are part of the endosomal-lysosomal system.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…The ability of neuronal lysosomes to maintain a low luminal pH occurs during aging as a consequence of oxidative impairment of membrane vesicular ATPases (Colacurcio and Nixon, 2016). Indeed, HNE can impair lysosome function in cerebral cortical neurons, resulting in the accumulation of undegraded cargos and subsequent cell death (Zhang et al, 2017).…”

Emerging Roles for the Lysosome in Lipid Metabolism

“…Loss of lysosomal function is emerging as a driving force in age-related degeneration of cells and tissues (Colacurcio and Nixon, 2016, Hughes and Gottschling, 2012). A time dependent decrease in autophagic flux progressively impairs cellular homeostasis, as evidenced by accumulation of aggregated proteins and extensive mitochondrial damage observed in brain tissue from healthy aged subjects.…”