Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator involved in mitochondrial biogenesis, oxidative stress response, and energy metabolism. PGC-1α is part of an energy sensing network that translates environmental influences into alterations in gene expression of mainly mitochondrial molecular pathways. A role in neuroprotection has been implicated for PGC-1α in the context of mitochondrial expression networks.
Our research group has previously established a transgenic mouse line with stable overexpression of PGC-1α in brain neurons. Transgenic overexpression of PGC-1α is associated with an enhanced functional state of mitochondrial energy production. In the context of neurodegenerative processes, brain neurons of PGC-1α transgenic mice are protected against oxidative stressors in the MPTP mouse model of Parkinson's Disease.
To further characterize the transcriptional activity of PGC-1α regulated gene networks in brains of transgenic mice, a quantitative real-time PCR based system was established. Gene expression was measured for a subset of genes found to be differentially regulated in a microarray based screening of RNA obtained from hippocampus and cortex of PGC-1α transgenic mice.
Increased PGC-1α gene expression was found in hippocampus and cortex of PGC-1α transgenic mice, and their translation into protein was confirmed immunohistochemically. Expression analysis revealed significant changes in mRNA levels of PGC-1α controlled molecular pathways involved in mitochondrial energy production and antioxidant responses. Furthermore, alterations in the expression of some non-mitochondrial genes with established links to neurodegeneration were observed. Furthermore, a change in GABAA receptor subunit expression was detected.
In accordance with previous studies on the PGC-1α transgenic mouse line, these findings suggest that differential gene expression associated with PGC-1α overexpression contributes to an enhanced functional state of neurons in hippocampus and cortex of PGC-1α transgenic mice.
Increased knowledge about the transcriptional modulation of neuronal genes regulated by PGC-1α can lead to better insights into mechanisms governing neurodegeneration and neuroprotective pathways. Pharmacological modulation of PGC-1α activity may be a feasible approach for neuroprotective treatments in neurodegenerative diseases, such as Parkinson's Disease.
