PGC-1 Alpha as a Neuroprotective Target in Parkinsonís Disease
Target Validation, 2007
Many treatments exist that can help to treat the symptoms of Parkinson's disease. But despite these "Symptoms & Side Effects" treatments, the disease continues to progress, with ongoing loss of specific sets of brain cells. The primary goal of this proposal is to test the possibility that increasing the activity of a molecule known as "PGC-1alpha" can prevent the degeneration of brain cells in Parkinson's disease.
Activity of the mitochondria, the "energy factories" of our cells, is impaired in PD. A consequence of this mitochondrial impairment is an increased production of highly damaging molecules called "free radicals". Free radical damage, known as “oxidative stress” is greatly increased in the brain in PD. PGC-1alpha is a molecule that coordinates the expression of other genes needed to synthesize new mitochondria, and simultaneously increases expression of several genes involved in protection against oxidative stress, making it a highly attractive target for protecting brain cells in PD. We propose to test this possibility by using a “gene therapy” approach in which a modified virus is used to deliver the gene for PGC-1alpha into a vulnerable brain region in pre-clinical models of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If these studies show that increasing PGC-1alpha levels in vulnerable regions of the brain is beneficial, then it may be possible eventually to test similar gene therapy strategies to increase PGC-1alpha in clinical trials in Parkinson’s disease patients. A limitation of this technique is that it requires a surgical method to inject the virus carrying the gene into the brain. However, PGC-1alpha is a highly inducible molecule, and it is hoped that eventually agents can be identified that can be used orally to increase PGC-1alpha activity without requiring surgical interventions.
These studies will determine whether or not increasing the activity of PGC-1alpha in a vulnerable region in the brain leads to protection against the degeneration of brain cells in animal models of Parkinson’s disease. It successful, then these data eventually may lead to clinical trials to test similar strategies in PD patients.
INTERIM PROGRESS REPORT
Mitochondrial dysfunction and oxidative stress play important roles in Parkinson’s disease (PD). PGC-1alpha is a transcriptional coactivator that regulates genes necessary for mitochondrial biogenesis, and also upregulates many antioxidant gene activities. We therefore hypothesized the overexpression of PGC-1alpha would protect in pre-clinical models of PD. To test this, we overexpressed PGC-alpha in the substantia nigra (SN) of mice by unilateral stereotaxic injections using a viral vector, AAV10-PGC-1alpha or a control vector (AAV10-mCherry). We confirmed overexpression of PGC-alpha and its target genes. However, unexpectedly, we found substantial toxicity associated with PGC-1alpha overexpression based on amphetamine-induced rotational behavior, levels of striatal dopamine and metabolites, striatal tyrosine hydroxylase (TH) immunostaining intensity, and stereological counts of TH+ SN neurons. The toxicity was not due to the stereotaxic injection itself or the AAV viral vector as we did not detect toxicity from AAV-mCherry injections. These results may have implications in terms of the potential for upregulation as a neuroprotective strategy in PD. Additional studies are underway to investigate potential mechanisms of toxicity of PGC-1alpha, as well as the possibility that lower levels of overexpression of PGC-1alpha may be protective.
Mitochondrial dysfunction may play a role in Parkinson’s disease (PD). Levels of PGC-1α, a key regulator of mitochondrial synthesis, are low early in PD. We hypothesized that increasing PGC-1α activity may be protective. To test this, we injected a modified virus carrying the PGC-1α gene into a brain region affected in PD. To our surprise, PGC-1α expression failed to protect against a mitochondrial toxin (MPTP). Furthermore, PGC-1α on its own caused a dramatic decrease in expression of a key enzyme involved dopamine synthesis (tyrosine hydroxlase; TH), as well as a decrease in a potentially protective protein (BDNF). Similar but less severe effects were seen when lower levels of the virus were injected. These effects are not accounted for by a nonspecific effect of the virus, as they are absent with a control viral injection. Although reduced PGC-1α activity may play a role in PD, our data indicate a need for caution in attempts to upregulate PGC-1α activity, and suggest that a focus on normalization (rather than more aggressive upregulation) may be optimal. We are now investigating potential mechanisms of these effects of PGC-1α in order to guide attempts to maximize the neuroprotective potential of this target.
Presentations & Publications
• Clark J, Silvaggi JM, Bass C, Simon DK. Effects of PGC-1a over-expression on the substantia nigra. Society for Neuroscience. November 15, 2011. Washington D.C.
• Joanne Clark. PGC-1α as a neuroprotective target in Parkinson’s disease. Boston Aging Data Club Series, sponsored by the Paul F. Glenn Laboratories for the Biological Mechanisms of Aging; Harvard Medical School. November 1, 2011. Boston, MA.
• Joanne Clark. Neuroprotection in Parkinson’s disease: is PGC-1a a viable target? Bauer Forum. June 29, 2011. FAS Center for Systems Biology. Harvard University. Cambridge. Massachusetts.
• Clark J, Silvaggi JM, Bass C, Spiegelman BM, Simon DK. PGC-1a Overexpression Strategies for Neuroprotection in Parkinson’s disease. Society for Neuroscience. October 17-21, 2009. Chicago IL.
• Clark J, Silvaggi JM, Bass C, Zheng K, Spiegelman BM, Simon DK. Potential neuroprotective effects of targeted PGC-1a overexpression in the mouse substantia nigra. Society for Neuroscience. November 3-7, 2007. San Diego CA.
Associate Professor at Beth Israel Deaconess Medical Center and Harvard Medical School
Location: Boston, United States