ArticleAging cell2021
Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.
Article in Aging cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 24 citations in OpenAlex.
- A paradoxical relationship between mitochondrial calcium regulation and retinal ganglion cell degeneration after axon damage.bioRxiv : the preprint server for biology · 2026Article
- Identification of presenilin mutations that have sufficient gamma-secretase proteolytic activity to mediate Notch signaling but disrupt organelle and neuronal health.Neurobiology of disease · 2025Article
- Identification of Plasma Cell Subsets and Molecular Markers of Alzheimer's Disease Based on Single-Cell Weighted Gene Co-Expression Network Analysis, Mendelian Randomization Analysis and Clinical Validation.International journal of general medicine · 2025Article
- Mitochondrial Quality Control in Alzheimer's Disease: Insights fromAntioxidants (Basel, Switzerland) · 2024Review
- Article
- C. elegans Presenilin Mediates Inter-Organelle Contacts and Communication that Is Required for Lysosome Activity.Aging and disease · 2024Article
- A familial Alzheimer's disease associated mutation in presenilin-1 mediates amyloid-beta independent cell specific neurodegeneration.PloS one · 2024Article
- Article
- Deregulation of Mitochondrial Calcium Handling Due to Presenilin Loss Disrupts Redox Homeostasis and Promotes Neuronal Dysfunction.Antioxidants (Basel, Switzerland) · 2022Article
- Modeling Alzheimer's Disease inBiomedicines · 2022Review
- Increased mitochondrial calcium uptake and concomitant mitochondrial activity by presenilin loss promotes mTORC1 signaling to drive neurodegeneration.Aging cell · 2021Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Metabolic dysfunction and protein aggregation are common characteristics that occur in age-related neurodegenerative disease. However, the mechanisms underlying these abnormalities remain poorly understood. We have found that mutations in the gene encoding presenilin in Caenorhabditis elegans, sel-12, results in elevated mitochondrial activity that drives oxidative stress and neuronal dysfunction. Mutations in the human presenilin genes are the primary cause of familial Alzheimer's disease. Here, we demonstrate that loss of SEL-12/presenilin results in the hyperactivation of the mTORC1 pathway. This hyperactivation is caused by elevated mitochondrial calcium influx and, likely, the associated increase in mitochondrial activity. Reducing mTORC1 activity improves proteostasis defects and neurodegenerative phenotypes associated with loss of SEL-12 function. Consistent with high mTORC1 activity, we find that SEL-12 loss reduces autophagosome formation, and this reduction is prevented by limiting mitochondrial calcium uptake. Moreover, the improvements of proteostasis and neuronal defects in sel-12 mutants due to mTORC1 inhibition require the induction of autophagy. These results indicate that mTORC1 hyperactivation exacerbates the defects in proteostasis and neuronal function in sel-12 mutants and demonstrate a critical role of presenilin in promoting neuronal health.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.