A Role for Presenilins in Autophagy Revisited: Normal Acidification of Lysosomes in Cells Lacking PSEN1 and PSEN2
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Presenilins 1 and 2 (PS1 and PS2) are the catalytic subunits of the γ-secretase complex, and genes encoding mutant PS1 and PS2 variants cause familial forms of Alzheimer's disease. Lee et al. (2010) recently reported that loss of PS1 activity lead to impairments in autophagosomal function as a consequence of lysosomal alkalinization, caused by failed maturation of the proton translocating V0a1 subunit of the vacuolar (H+)-ATPase and targeting to the lysosome. We have reexamined these issues in mammalian cells and in brains of mice lacking PS (PScdko) and have been unable to find evidence that the turnover of autophagic substrates, vesicle pH, V0a1 maturation, or lysosome function is altered compared with wild-type counterparts. Collectively, our studies fail to document a role for presenilins in regulating cellular autophagosomal function. On the other hand, our transcriptome studies of PScdko mouse brains reveal, for the first time, a role for PS in regulating lysosomal biogenesis.
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There are inconsistent views on a series of events caused by defects in PS1, including impaired maturation of V0a1 in lysosomes, V-ATPase dysfunction, and lysosomal acidification defects.
“However, there are inconsistent views on a series of events caused by defects in PS1, including impaired maturation of V0a1 in lysosomes, V-ATPase dysfunction, and lysosomal acidification defects.267,268”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [267]
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References 45 · Cited by 122
- Authors
- Zhang, X., Garbett, K., Veeraraghavalu, K., Wilburn, B., Gilmore, R., Mirnics, K., & Sisodia, S. S.
- Affiliations
- University of Chicago (US)
- Vanderbilt University (US)
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Sisodia, S. S.
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-06-20
- Volume
- 32
- Issue
- 25
- Pages
- 8633-8648
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3467018
- OpenAlex
- W2097088035
- Cited by
- 122
- References
- 45
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 5 · 2022: 9 · 2021: 7 · 2020: 11 · 2019: 9 · 2018: 6 · 2017: 6 · 2016: 10 · 2015: 9 · 2014: 11 · 2013: 15 · 2012: 7
- FWCI
- 10.03
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cure Alzheimer's Fund
- Eisai
- National Institutes of Health
- National Institute on Aging (R01AG040185, R01AG021494, P01AG014248)
- Topics
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Physiology › Calcium signaling and nucleotide metabolism
- Keywords
- presenilin, presenilin 1, presenilin 2, gamma-secretase, autophagy, lysosomal acidification, lysosomal alkalinization, vacuolar H+-ATPase, lysosomal biogenesis, Alzheimer's disease, transcriptome
- MeSH terms
- Animals, Autophagy, Blastocyst, Cathepsin D, Cells, Cultured, Humans, Hydrogen-Ion Concentration, Lysosomes, Neurons, RNA, Blotting, Western, Gene Expression, Polymerase Chain Reaction, DNA Primers, Mice, Knockout, Vacuolar Proton-Translocating ATPases, RNA, Small Interfering, Cell Line, Tumor, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Presenilins, Presenilin-1, Presenilin-2
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