Downregulation of NF-κB signaling by mutant huntingtin proteins induces oxidative stress and cell death |
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Authors: | Sami Reijonen Jyrki P Kukkonen Alise Hyrskyluoto Jenny Kivinen Minna Kairisalo Nobuyuki Takei Dan Lindholm Laura Korhonen |
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Institution: | (1) Minerva Medical Research Institute, Biomedicum Helsinki, Tukholmankatu 8, 00290 Helsinki, Finland;(2) Unit of Biochemistry and Cell Biology, Department of Veterinary Biosciences, University of Helsinki, Post Box 66, 00014 University of Helsinki, Finland;(3) Department of Molecular Neurobiology, Brain Research Institute, Niigata University, Niigata, Japan;(4) Division of Child Psychiatry, Helsinki University Central Hospital, Post Box 280, 00029 HUS, Finland; |
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Abstract: | 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-κB-p65 (NF-κB-p65) protein decreased. Downregulation
of NF-κB 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-κB-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-κB-p65
signaling are crucial factors involved in oxidative stress and cell death mediated by mutant huntingtin proteins. |
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