Mitochondrial dysfunction and oxidative stress occur in Parkinson's disease (PD), but little is known about the molecular mechanisms controlling these events. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) is a transcriptional coactivator that is a master regulator of oxidative stress and mitochondrial metabolism. We show here that transgenic mice overexpressing PGC-1α in dopaminergic neurons are resistant against cell degeneration induced by the neurotoxin MPTP. The increase in neuronal viability was accompanied by elevated levels of mitochondrial antioxidants SOD2 and Trx2 in the substantia nigra of transgenic mice. PGC-1α overexpression also protected against MPTP-induced striatal loss of dopamine, and mitochondria from PGC-1α transgenic mice showed an increased respiratory control ratio compared with wild-type animals. To modulate PGC-1α, we employed the small molecular compound, resveratrol (RSV) that protected dopaminergic neurons against the MPTP-induced cell degeneration almost to the same extent as after PGC-1α overexpression. As studied in vitro, RSV activated PGC-1α in dopaminergic SN4741 cells via the deacetylase SIRT1, and enhanced PGC-1α gene transcription with increases in SOD2 and Trx2. Taken together, the results reveal an important function of PGC-1α in dopaminergic neurons to combat oxidative stress and increase neuronal viability. RSV and other compounds acting via SIRT1/PGC-1α may prove useful as neuroprotective agents in PD and possibly in other neurological disorders.

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.

No abstract

X chromosome-linked inhibitor of apoptosis protein (XIAP) is an anti-apoptotic protein enhancing cell survival. Brain-derived neurotrophic factor (BDNF) also promotes neuronal viability but the links between XIAP and BDNF have remained unclear. We show here that the overexpression of XIAP increases BDNF in transgenic mice and cultured rat hippocampal neurons, whereas downregulation of XIAP by silencing RNA decreased BDNF. XIAP also stimulated BDNF signaling, as shown by increased phosphorylation of the TrkB receptor and the downstream molecule, cAMP response element-binding protein. The mechanism involved nuclear factor-kappaB (NF-kappaB) activation and blocking of NF-kappaB signaling inhibited the increased activities of BDNF promoters I and IV by XIAP. In neuronal cultures XIAP also upregulated interleukin (IL)-6, which is an NF-kappaB-responsive gene. The addition of IL-6 elevated whereas incubation with IL-6-blocking antibodies reduced BDNF in the neurons. BDNF itself activated NF-kappaB in the neurons at higher concentrations. The data show that XIAP has trophic effects on hippocampal neurons by increasing BDNF and TrkB activity. The results reveal a cytokine network in the brain involving BDNF, IL-6 and XIAP interconnected via the NF-kappaB system.

Resveratrol, a polyphenol derived e.g. from red grapes, has been shown to mediate several positive biological actions such as protection of cells against oxidative stress. It can also influence cell signaling, but the mechanisms behind its antioxidant properties are largely unknown. Here we show that RSV reduces oxidative stress and enhances cell survival in PC6.3 cells depending on the concentration. In these cells, RSV increased the levels of antioxidants, SOD2 and TRX2, and of X chromosome-linked inhibitor of apoptosis protein. RSV also activated NFκB signaling as shown using luciferase reporter constructs. These findings show that RSV regulates oxidative stress and mitochondrial antioxidants in neuronal cells. This may contribute to cell protection in various brain disorders.