期刊
EXPERIMENTAL NEUROLOGY
卷 250, 期 -, 页码 143-150出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.expneurol.2013.09.001
关键词
Neuroprotection; Oxidative stress; Endoplasmic reticulum; Alzheimer's disease; Intracellular calcium
资金
- National Eye Institute [EY014227, EY022774]
- Institute on Aging [AG010485, AG022550, AG027956]
- National Center for Research Resources
- National Institute of General Medical Sciences of the National Institutes of Health [RR022570, RR027093]
- Felix and Carmen Sabates Missouri Endowed Chair in Vision Research
- Vision Research Foundation of Kansas City
- Challenge Grant from Research to Prevent Blindness
Presenilins (PS), endoplasmic reticulum (ER) transmembrane proteins, form the catalytic core of gamma-secretase, an amyloid precursor protein processing enzyme. Mutations in PS lead to Alzheimer's disease (AD) by altering gamma-secretase activity to generate pathologic amyloid beta and amyloid plaques in the brain. Here, we identified a novel mechanism where binding of a soluble, cytosolic N-terminal domain fragment (NTF) of PS to intracellular Ca2+ release channels, ryanodine receptors (RyR), controls Ca2+ release from the ER While PS1NTF decreased total RyR-mediated Ca2+ release, PS2NTF had no effect at physiological Ca2+ concentrations. This differential function and isotype-specificity is due to four cysteines absent in PS1NTF, present, however, in PS2NTF. Site-directed mutagenesis targeting these cysteines converted PS1NTF to PS2NTF function and vice versa, indicating differential RyR binding. This novel mechanism of intracellular Ca2+ regulation through the PS-RyR interaction represents a novel target for AD drug development and the treatment of other neurodegenerative disorders that critically depend on RyR and PS signaling. (C) 2013 Elsevier Inc. All rights reserved.
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