Parkinson's disease (PD) is the second most common neurodegenerative disease in the United States yet the currently available treatment options are unable to alter disease progression. Mitochondrial dysfunction has long been suspected to play a pathogenic role in PD, however, it was the discovery of mutations in PINK1, which encodes a mitochondrial kinase, as a cause of autosomal recessive PD that established a strong genetic link between PD and mitochondria. Emerging evidence strongly implicates abnormal mitochondrial dynamics as an important factor in pathogenesis;a cellular pathway in which PINK1 plays a central role. Recently, we provided evidence that PINK1 mutations induce mitochondrial fragmentation by altering the levels of fission/fusion proteins. Overexpression of the kinase-dead PINK1L347P mutant in dopaminergic neuronal cells led to increased recruitment of the fission protein Drp1 to mitochondria with concomitant reduction in the fusion protein Mfn2. In addition to these structural changes, there was also significant loss of mitochondrial membrane potential and intracellular ATP levels. Even more interesting, these mitochondrial structural and functional abnormalities could be rescued by blocking endogenous Drp1 function with mdivi-1, a small- molecule inhibitor of Drp1, or through overexpression of the dominant negative mutant Drp1K38A. The overall goal of this proposal is to further investigate these mechanisms and establish their in vivo significance. To this end I will explore the therapeutic potential of mitochondrial fission inhibition using pharmacologic and genetic strategies in mouse models of nigrostriatal dysfunction and degeneration. I will employ the in vivo use of mdivi- 1 and a recombinant adeno-associated virus containing transcription units encoding Drp1K38A as my primary interventions. Specifically, I propose to explore (1) the potential of mitochondrial fission inhibition to ameliorate nigrostriatal dysfunction in Pink1-/- mice, (2) explore abnormal mitochondrial dynamics as a potential mechanism underlying the nigrostriatal synaptic dysfunction in Pink1-/- mice through use of primary mesencephalic dopaminergic neuronal cultures, and (3) To investigate the neuroprotective potential of inhibiting mitochondrial fission in a murine MPTP model of PD. The combination of the complementary in vivo and in vitro approaches in this proposal holds great potential not only for providing valuable proof-of-principle data regarding the pre-clinical evaluation of a novel therapeutic target in PD as well as detailed basic science exploration of underlying mechanisms, but our proposed experiments involving the rescue of an already dysfunctional or lesioned system bring significantly more clinical relevance to this proposal.

Public Health Relevance

Parkinson's disease (PD) is the second most common neurodegenerative disease in the United States yet the currently available treatment options are unable to alter disease progression. Emerging evidence strongly implicates abnormal mitochondrial dynamics as an important factor in pathogenesis, though the underlying mechanisms are incompletely understood. Nevertheless, the manipulation of these mitochondrial fission and fusion pathways constitutes a potentially significant and novel therapeutic target in PD. My proposal aims to further explore how impairments in mitochondrial dynamics lead to neuronal dysfunction and evaluate in vivo the therapeutic utility of targeting this pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30AG040903-01
Application #
8200127
Study Section
Special Emphasis Panel (ZRG1-F02B-M (20))
Program Officer
Chen, Wen G
Project Start
2011-09-20
Project End
2014-08-01
Budget Start
2011-09-20
Budget End
2012-09-19
Support Year
1
Fiscal Year
2011
Total Cost
$46,800
Indirect Cost
Name
University of Rochester
Department
Neurology
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Rappold, Phillip M; Cui, Mei; Grima, Jonathan C et al. (2014) Drp1 inhibition attenuates neurotoxicity and dopamine release deficits in vivo. Nat Commun 5:5244
Rappold, Phillip M; Cui, Mei; Chesser, Adrianne S et al. (2011) Paraquat neurotoxicity is mediated by the dopamine transporter and organic cation transporter-3. Proc Natl Acad Sci U S A 108:20766-71