Epidemiological, genetic, and biological evidence implicates mitochondrial dysfunction in the pathogenesis of Parkinson Disease (PD). Recent transcriptional studies have identified clusters of genes reduced in dopaminergic neurons of the substantia nigra of patients with subclinical and symptomatic PD, the majority of which are involved in neuronal metabolism and mitochondrial function. These findings raise the possibility that the function of transcriptional regulators of metabolic and mitochondrial genes may be compromised in idiopathic PD and that targeting key transcriptional pathways for gene regulation may be an appropriate strategy for preventing and/or rescuing metabolic deficits and neuronal cell death. Using bioinformatics and transcriptional assays, we have identified a potential transcription factor required for the regulation of metabolic and nuclear-encoded gene transcription in dopaminergic nigral neurons. This protein, estrogen-related receptor ? (ERR?), drives the expression of nuclear-encoded genes for mitochondrial biogenesis and respiration in peripheral tissues, and it can directly associate with peroxisome proliferator- activated receptor ? coactivator 1? (PGC-1?), a transcriptional coactivator that is reduced in PD and can be neuroprotective when overexpressed in PD models. Our preliminary data indicate that ERR? is expressed by neurons of the substantia nigra in rodents and that deletion of ERR? from the mouse midbrain causes a reduction in ERR?-driven metabolic genes and motor activity. Furthermore, our data indicate that PGC-1?- target genes are enriched in binding sites for ERR? and that PGC-1? and ERR? can synergistically drive mitochondrial gene expression. Importantly, the majority of mitochondrial genes of the electron transport chain reduced in PD are ERR? target genes. The experiments proposed in this application will expand upon these initial findings to test the hypotheses that ERR? is a central regulator of metabolic and mitochondrial gene expression in nigral neurons (Aim 1), that ERR? is required for PGC-1? to induce metabolic and mitochondrial genes (Aim 2), and that overexpression of ERR? can prevent cell dysfunction and death in rodent model of PD (Aim 3). These experiments have the potential to reveal the critical pathways by which nigral neurons maintain metabolic and mitochondrial homeostasis and a novel avenue for improving mitochondrial function in disease. Furthermore, considering that ERR? can orchestrate a transcriptional program for a number of genes reduced in PD, ERR? deletion in nigral neurons could serve as a biologically relevant model of idiopathic PD.
Mitochondrial dysfunction is a central feature of neurodegenerative disorders. This proposal aims to elucidate key pathways for the expression of metabolic and mitochondrial genes in neurons, with the ultimate goal of identifying novel approaches to enhance neuronal function and survival in neurodegeneration.
|McMeekin, Laura J; Li, Ye; Fox, Stephanie N et al. (2018) Cell-Specific Deletion of PGC-1? from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment. J Neurosci 38:3273-3286|