Cited by 548Autophagy in Disease and TherapyATP Synthase and ATPases ResearchCalcium signaling and nucleotide metabolism

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

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Colacurcio, Daniel J., Nixon, Ralph A.·2016·Ageing Research Reviews

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 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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Crossref · 10.1016/j.arr.2016.05.004

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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 measured
  • Mutations 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).”
  • 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.”

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Research works printed but not linked: 6

  1. Dehay B Martinez-Vicente M Ramirez A Perier C Klein C Vila M Bezard E Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove. Autophagy 2012a 8 1389 1391 22885599 PMC3442887
  2. Lee JH Yu WH Kumar A Lee S Mohan PS Peterhoff CM Wolfe DM Martinez-Vicente M Massey AC Sovak G Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by Alzheimer-related PS1 mutations. Cell 2010b 141 1146 1158 20541250 PMC3647462
  3. Nixon RA The role of autophagy in neurodegenerative disease. Nature medicine 2013b 19 983 997 23921753
  4. Torres M Jimenez S Sanchez-Varo R Navarro V Trujillo-Estrada L Sanchez-Mejias E Carmona I Davila JC Vizuete M Gutierrez A Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus. Mol Neurodegener 2012 7 59 23173743 PMC3575255
  5. Vinicia AP Hongmei L Heidi MS Baiping W Li Y Yin X Daniel BS Michela P Alberto R Virginia M- YL Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB. EMBO Molecular Medicine 2014 6 1142 1160 25069841 PMC4197862
  6. Wolfe DM Lee JH Kumar A Lee S Orenstein SJ Nixon RA Autophagy failure in Alzheimer's disease and the role of defective lysosomal acidification. Eur J Neurosci 2013b 37 1949 1961 23773064 PMC3694736

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Authors
Colacurcio, D. J., & Nixon, R. A.
Affiliations
Nathan Kline Institute for Psychiatric Research (US)
Corresponding author
Nixon, Ralph A.
Venue
Ageing Research Reviews
Publisher
Elsevier BV
Published
2016-12
Volume
32
Pages
75-88
ISSN
1568-1637 (ISSN-L)
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
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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