Presenilin-1 mutations sensitize neurons to DNA damage-induced death by a mechanism involving perturbed calcium homeostasis and activation of calpains and caspase-12.
Mutations in presenilin-1 (PS1) can cause early onset familial Alzheimer's disease (AD). Studies of cultured cells and mice expressing mutant PS1 suggest that PS1 mutations may promote neuronal dysfunction and degeneration by altering cellular calcium homeostasis. On the other hand, it has been suggested that age-related damage to DNA in neurons may be an important early event in the pathogenesis of AD. We now report that PC12 cells and primary hippocampal neurons expressing mutant PS1 exhibit increased sensitivity to death induced by DNA damage. The hypersensitivity to DNA damage is correlated with increased intracellular Ca(2+) levels, induction of p53, upregulation of the Ca(2+)-dependent protease m-calpain, and mitochondrial membrane depolarization. Moreover, activation of caspase-12, an endoplasmic reticulum (ER)-associated caspase, is greatly increased in cells expressing mutant PS1. DNA damage-induced death of cells expressing mutant PS1 was attenuated by inhibitors of calpains I and II, by an intracellular Ca(2+) chelator, by the protein synthesis inhibitor cycloheximide, and by a broad-spectrum caspase inhibitor, but not by an inhibitor of caspase-1. Agents that release Ca(2+) from the ER increased the vulnerability of cells expressing mutant PS1 to DNA damage. By promoting ER-mediated apoptotic proteolytic cascades, PS1 mutations may sensitize neurons to DNA damage.
Chan
Sic L
SL
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA.
Culmsee
Carsten
C
Haughey
Norman
N
Klapper
Wolfram
W
Mattson
Mark P
MP
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D016716:PC12 Cells; D053764:Presenilin-1; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D008565:Membrane Proteins; D053764:Presenilin-1; D016159:Tumor Suppressor Protein p53; D002154:Calpain; C506440:Casp12 protein, mouse; C506443:Casp12 protein, rat; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053454:Caspase 12; D053148:Caspase 3; D020169:Caspases; D002118:Calcium