Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease
Open accessAbstract
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 hydrolysis 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.
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CTSD activation is deficient in various neuropathologic states and as a result of genetic mutations.
“CTSD activation is deficient in various neuropathologic states and as a result of genetic mutations (Colacurcio and Nixon, 2016;Vidoni et al., 2016).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Colacurcio and Nixon, 2016
Section 2.2 (page unavailable) reports impaired cathepsin activation in glial cells expressing mutant APP and impaired cathepsin function or maturation in other genetic models of neurological disease. Section 1.2 identifies cathepsin D as an acid-dependent protease, but the disease passages do not establish that the impaired activation is specifically CTSD activation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredMutations or imbalance of the subunits or accessory proteins composing the proton pump impair acidification and lead to neurodegeneration in numerous congenital diseases.
“Mutations or imbalance of the subunits or accessory proteins composing the proton pump impair acidification and lead to neurodegeneration in numerous congenital diseases (Colacurcio and Nixon, 2016).”
From Lysosomal Dysfunction in Down Syndrome Is APP-Dependent and Mediated by APP-βCTF (C99) (2019) · cites this paper as Colacurcio and Nixon, 2016
The i3N-iPSC line can be efficiently differentiated into homogeneous glutamatergic neurons in a highly scalable manner.
“which can be efficiently differentiated into homogenous glutamatergic neurons in a highly scalable manner9 (i3N-iPSC, Fig. 1a).”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [9]
The parental iPSC line used was WTC11 iPSCs carrying a single-copy doxycycline-inducible mouse NGN2 at the AAVS1 locus.
“WTC11 iPSCs harboring a single-copy of doxycycline-inducible mouse NGN2 at the AAVS1 locus (Ngn2-iPSCs,9) were used as the parental iPSC line for further genetic engineering.”
From Genome-wide CRISPRi/a screens in human neurons link lysosomal failure to ferroptosis (2021) · cites this paper as [9]
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Flagged first, then by citations
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Klionsky, D. J., Abdel-Aziz, A. K., Abdelfatah, S., Abdellatif, M., Abdoli, A., Abel, S., Abeliovich, H., Abildgaard, M. H., Abudu, Y. P., Acevedo-Arozena, A., et al. (2021) · Autophagy · doi:10.1080/15548627.2020.1797280 · Cited by 2,622 · see citing works
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“Upon fusion with autophagosomes, lysosomal proteolytic enzymes carry out substrate degradation, while vesicular or vacuolar-type ATPase (V-ATPase) mediates acidification of the compartment (Colacurcio & Nixon, 2016).”
BackgroundCa2+ Dyshomeostasis Disrupts Neuronal and Synaptic Function in Alzheimer’s Disease
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Peroxisomal defects in microglial cells induce a disease-associated microglial signature
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- Authors
- Colacurcio, D. J., & Nixon, R. A.
- Affiliations
- Nathan Kline Institute for Psychiatric Research (US)
- Corresponding author
- Nixon, Ralph A.
- ORCID
- Nixon, Ralph A.
- Venue
- Ageing Research Reviews
- Publisher
- Elsevier BV
- Published
- 2016-12
- Volume
- 32
- Pages
- 75-88
- ISSN
- 1568-1637 (ISSN-L)
- PMC
- PMC5112157
- OpenAlex
- W2401710715
- Cited by
- 548
- References
- 241
- Citations by year
- 2026: 71 · 2025: 80 · 2024: 55 · 2023: 60 · 2022: 57 · 2021: 56 · 2020: 72 · 2019: 39 · 2018: 32 · 2017: 22 · 2016: 4
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ageing Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- US National Institute on Aging (P01AG017617, R01AG005604)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- V-ATPase, lysosomal acidification, lysosomal pH, cellular aging, neurodegenerative diseases, Parkinson's disease, Alzheimer's disease, autophagy, endocytosis, lysosomal dysfunction, neuronal vulnerability, nutrient sensing, lysosomal hydrolysis, familial neurodegenerative disease
- MeSH terms
- Aging, Autophagy, Humans, Lysosomes, Signal Transduction, Neurodegenerative Diseases, Vacuolar Proton-Translocating ATPases, Caloric Restriction
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