Transcribe to survive: transcriptional control of antioxidant defense programs for neuroprotection in Parkinson's disease

Abstract

Parkinson's disease (PD) is a progressive, primarily motor disorder that is characterized by loss of dopaminergic (DA) neurons within the substantia nigra (SN). Cell death in PD has been associated with impaired mitochondrial function and increased oxidative stress. Strategies to reduce the oxidative load in DA cells may be beneficial in slowing the progression of PD. The transcription factor nuclear factor-erythroid 2 (NF-E2) related factor 2 (NRF2) is emerging as a master regulator of antioxidant defense systems, which makes it an attractive target for manipulations that aim to increase cellular resistance to oxidative stress. Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC1alpha) is a regulator of mitochondrial biogenesis genes that simultaneously upregulates many genes known to protect against oxidative stress. Pgc-1alpha knockout mice show enhanced susceptibility to SN neuronal loss following MPTP exposure, whilst overexpression of Pgc-1alpha appears to protect against oxidative stress in vitro. This makes PGC-1alpha a highly attractive target for neuroprotective therapies in PD. This review will explore the mechanisms behind the induction of NRF2 and PGC-1alpha in response to oxidative stress and identify common pathways that may provide targets for upregulating antioxidant defense programs.