Calbindin D28k blocks the proapoptotic actions of mutant presenilin 1: reduced oxidative stress and preserved mitochondrial function.
Mutations in the presenilin 1 (PS-1) gene account for many cases of early-onset autosomal dominant inherited forms of Alzheimer's disease. Recent findings suggest that PS-1 mutations may sensitize neurons to apoptosis induced by trophic factor withdrawal and exposure to amyloid beta-peptide (Abeta). We now report that overexpression of the calcium-binding protein calbindin D28k prevents apoptosis in cultured neural cells expressing mutant PS-1 (L286V and M146V missense mutations). Elevations of the intracellular Ca2+ concentration and generation of reactive oxygen species induced by Abeta, and potentiated by mutant PS-1, were suppressed in calbindin-overexpressing cells. Impairment of mitochondrial function by Abeta (which preceded apoptosis) was exacerbated by PS-1 mutations and was largely prevented by calbindin. These findings suggest that PS-1 mutations render neurons vulnerable to apoptosis by a mechanism involving destabilization of cellular calcium homeostasis, which leads to oxidative stress and mitochondrial dysfunction.
Guo
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Q
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, USA.
Christakos
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Robinson
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N
Mattson
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MP
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D064092:Calbindin 1; D064026:Calbindins; D002118:Calcium / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics*; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D018384:Oxidative Stress; D016716:PC12 Cells; D053764:Presenilin-1; D051381:Rats; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins / Q000096:biosynthesis; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis* / Q000235:genetics
D016229:Amyloid beta-Peptides; C576500:Calb1 protein, rat; D064092:Calbindin 1; D064026:Calbindins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D053764:Presenilin-1; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D064030:S100 Calcium Binding Protein G; D002118:Calcium