Parkinson's disease (PD), the most frequent movement disorder, is caused by the progressive loss of the dopamine neurons within the substantia nigra pars compacta (SNc) and the associated deficiency of the neurotransmitter dopamine in the striatum. Post-mortem studies with PD brain tissue as well as the phenotypes of mice and flies lacking genes linked to recessive familial PD demonstrate that mitochondrial dysfunction and oxidative stress are important mechanisms underlying dopaminergic neuron death in both sporadic and familial PD. Peroxisome proliferator-activated receptor coactivator-11 (PGC-1a) is a transcriptional coactivator of nuclear receptors that stimulates mitochondrial biogenesis and function. PGC-1a induces the transcription of mitochondrial respiratory genes and increases expression of enzymes detoxifying reactive oxygen species, protecting cells against death caused by chronic reductions in adenosine triphosphate (ATP) synthesis and oxidative stress. PGC-1a knockout mice develop axonal and neuronal degeneration and display increased sensitivity to oxidative stressors affecting the SNc and the hippocampus, showing that endogenous PGC-1a protects against oxidative stress in the brain and is physiologically neuroprotective. In addition, we found that PGC-1a reduces rotenone- induced oxidative stress in neuronal cell. Collectively, these results suggest that PGC-1a is a prime candidate therapeutic protein for the treatment of neurodegenerative diseases that are caused by mitochondrial dysfunction and oxidative stress, such as PD and amyotrophic lateral sclerosis. Here we propose to test the hypothesis that boosting mitochondrial biogenesis and function through recombinant adeno-associated virus (rAAV)-mediated expression of PGC-1a in dopamine neurons of the SNc protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigrostriatal degeneration in mice, a well-established model of sporadic PD. Specifically, we will investigate: (1) whether rAAV-mediated expression of PGC-1a in the SNc inhibits dopamine neuron death and the decline of dopamine and its metabolites in the striatum of MPTP- treated mice;(2) whether ipsilateral nigral expression of PGC-1a results in contralateral, amphetamine-induced turning behavior in MPTP-treated mice, indicative of increased dopaminergic function of the rAAV- PGC-1a -injected hemisphere;and (3) whether viral-mediated expression of PGC-1a in dopamine neurons reduces overall protein nitration in the SNc and nitration of tyrosine hydroxylase and 1-synuclein in the striatum of MPTP-treated mice.
Mitochondrial dysfunction and oxidative stress are key mechanisms underlying the progressive death of nigral dopaminergic neurons and the development of Parkinson's disease (PD). This application proposes to investigate the efficacy of a protein, that both stimulates mitochondrial function and reduces oxidative stress, as a therapeutic target for the treatment of Parkinson's disease by using viral gene transfer in a mouse model of sporadic PD. If the experiments are successful, our project could impact public health by providing a target and its physiological pathway, for which stimulatory drugs could be screened in order to develop future therapies for PD and possibly other neurodegenerative and age-related disorders.
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| Akundi, Ravi S; Zhi, Lianteng; Sullivan, Patrick G et al. (2013) Shared and cell type-specific mitochondrial defects and metabolic adaptations in primary cells from PINK1-deficient mice. Neurodegener Dis 12:136-49 |
