期刊
GENETICS
卷 201, 期 4, 页码 1453-+出版社
GENETICS SOCIETY AMERICA
DOI: 10.1534/genetics.115.182808
关键词
Caenorhabditis elegans; calcium; endoplasmic reticulum; mitochondria; presenilin
资金
- National Institutes of Health (NIH) Office of Research Infrastructure Programs [P40 OD010440]
- Alzheimer's Association [NIRG-09-132122]
- NIH [GM088213]
Mutations in the presenilin (PSEN) encoding genes (PSEN1 and PSEN2) occur in most early onset familial Alzheimer's Disease. Despite the identification of the involvement of PSEN in Alzheimer's Disease (AD) similar to 20 years ago, the underlying role of PSEN in AD is not fully understood. To gain insight into the biological function of PSEN, we investigated the role of the PSEN homolog SEL-12 in Caenorhabditis elegans. Using genetic, cell biological, and pharmacological approaches, we demonstrate that mutations in sel-12 result in defects in calcium homeostasis, leading to mitochondrial dysfunction. Moreover, consistent with mammalian PSEN, we provide evidence that SEL-12 has a critical role in mediating endoplasmic reticulum (ER) calcium release. Furthermore, we found that in SEL-12-deficient animals, calcium transfer from the ER to the mitochondria leads to fragmentation of the mitochondria and mitochondrial dysfunction. Additionally, we show that the impact that SEL-12 has on mitochondrial function is independent of its role in Notch signaling, g-secretase proteolytic activity, and amyloid plaques. Our results reveal a critical role for PSEN in mediating mitochondrial function by regulating calcium transfer from the ER to the mitochondria.
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