Downregulation of NF-kappaB signaling by mutant huntingtin proteins induces oxidative stress and cell death.
Accumulation of abnormal proteins and endoplasmic reticulum stress accompany neurodegenerative diseases including Huntington's disease. We show that the expression of mutant huntingtin proteins with extended polyglutamine repeats differentially affected endoplasmic reticulum signaling cascades linked to the inositol-requiring enzyme-1 (IRE1) pathway. Thus, the p38 and c-Jun N-terminal kinase pathways were activated, while the levels of the nuclear factor-kappaB-p65 (NF-kappaB-p65) protein decreased. Downregulation of NF-kappaB signaling was linked to decreased antioxidant levels, increased oxidative stress, and enhanced cell death. Concomitantly, calpain was activated, and treatment with calpain inhibitors restored NF-kappaB-p65 levels and increased cell viability. The calpain regulator, calpastatin, was low in cells expressing mutant huntingtin, and overexpression of calpastatin counteracted the deleterious effects caused by N-terminal mutant huntingtin proteins. These results show that calpastatin and an altered NF-kappaB-p65 signaling are crucial factors involved in oxidative stress and cell death mediated by mutant huntingtin proteins.
Minerva Medical Research Institute, Biomedicum Helsinki, Tukholmankatu 8, 00290, Helsinki, Finland.
Sami
S
Reijonen
Jyrki P
JP
Kukkonen
Alise
A
Hyrskyluoto
Jenny
J
Kivinen
Minna
M
Kairisalo
Nobuyuki
N
Takei
Dan
D
Lindholm
Laura
L
Korhonen
D000818:Animals; D001483:Base Sequence; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D016923:Cell Death; D002460:Cell Line; D017931:DNA Primers / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D000071058:Huntingtin Protein; D024101:Mitochondrial Proteins / Q000378:metabolism; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D018384:Oxidative Stress; D016716:PC12 Cells; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D013879:Thioredoxins / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D000099156:Superoxide Dismutase 2
D002135:Calcium-Binding Proteins; D002154:Calpain; D017931:DNA Primers; D000071058:Huntingtin Protein; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D013482:Superoxide Dismutase; D013879:Thioredoxins; D051996:Transcription Factor RelA; D000099156:Superoxide Dismutase 2; C086055:HTT protein, human; C498143:RELA protein, human; C467002:TXN2 protein, human; C033668:calpastatin