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Presenilin 2 modulates endoplasmic reticulum (ER)–mitochondria interactions and Ca 2+ cross-talk
Open accessAbstract
Presenilin mutations are the main cause of familial Alzheimer's disease (FAD). Presenilins also play a key role in Ca 2+ homeostasis, and their FAD-linked mutants affect cellular Ca 2+ handling in several ways. We previously have demonstrated that FAD-linked presenilin 2 (PS2) mutants decrease the Ca 2+ content of the endoplasmic reticulum (ER) by inhibiting sarcoendoplasmic reticulum Ca 2+ -ATPase (SERCA) activity and increasing ER Ca 2+ leak. Here we focus on the effect of presenilins on mitochondrial Ca 2+ dynamics. By using genetically encoded Ca 2+ indicators specifically targeted to mitochondria (aequorin- and GFP-based probes) in SH-SY5Y cells and primary neuronal cultures, we show that overexpression or down-regulation of PS2, but not of presenilin 1 (PS1), modulates the Ca 2+ shuttling between ER and mitochondria, with its FAD mutants strongly favoring Ca 2+ transfer between the two organelles. This effect is not caused by a direct PS2 action on mitochondrial Ca 2+ -uptake machinery but rather by an increased physical interaction between ER and mitochondria that augments the frequency of Ca 2+ hot spots generated at the cytoplasmic surface of the outer mitochondrial membrane upon stimulation. This PS2 function adds further complexity to the multifaceted nature of presenilins and to their physiological role within the cell. We also discuss the importance of this additional effect of FAD-linked PS2 mutants for the understanding of FAD pathogenesis.
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“This finding, together with the generally accepted concept that mitochondrial deficits are key events in most neurodegenerative diseases (16, 17), and more specifically in AD (18, 19), led us to investigate the effect of presenilins on ER–mitochondria cross-talk.”
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Metadata
- Authors
- Zampese, E., Fasolato, C., Kipanyula, M. J., Bortolozzi, M., Pozzan, T., & Pizzo, P.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2011-02
- Volume
- 108
- Issue
- 7
- Pages
- 2777-2782
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2010550564
- Cited by
- 286
- References
- 3
- FWCI
- 12.33
- Type
- journal article
- Language
- en
- Open access
- green
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