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.

Background: LDLR is regulated by the E3 ubiquitin ligase Mylip/Idol. Results: FGF21 down-regulates Mylip/Idol expression and up-regulates its inhibitor Cnpy2/Msap. Conclusion: Increased LDLR by FGF21 results in increased lipoprotein uptake in human hepatocyte cells. Significance: The FGF21-mediated effect on cholesterol uptake is additive to that of statin, which may be of clinical significance.

The relevance of serine 5 phosphorylation of RNA polymerase II carboxy-terminal domain during initiation has been difficult to determine in mammalian cells as no general in vivo Ser5 kinase has been identified. Here, we demonstrate that deletion of the TFIIH kinase subunit Mat1 in mouse fibroblasts leads to dramatically reduced Pol II Ser5 phosphorylation. This is associated with defective capping and reduced Ser2 phosphorylation, decreased Pol II progression into elongation and severely attenuated transcription detected through analysis of nascent mRNAs, establishing a general requirement for mammalian Mat1 in transcription. Surprisingly, the general defect in Pol II transcription in Mat1−/− fibroblasts is not reflected in the majority of steady-state mRNAs. This indicates widespread stabilization of mRNAs and points to the existence of a regulatory mechanism to stabilize mRNAs following transcriptional attenuation, thus revealing a potential caveat in similar studies limited to analysis of steady-state mRNAs.