The maintenance of well-functioning mitochondria plays a key role in neuronal health. In the previous project period, we found that neuronal injury in several neurotoxin and genetic models of parkinsonian neurodegeneration converged on eliciting increased mitochondrial turnover by autophagy (mitophagy). While mitophagy in some models is neuroprotective, in other models, inhibiting autophagy reduces neurite retraction and cell death. We hypothesize that the capacity to replace damaged/degraded mitochondria through mitochondrial biogenesis is important in determining survival-death outcomes in this context. Preliminary data indicate a key role for extracellular signal-regulated protein kinase 2 (ERK2), which shows an altered mitochondrial distribution in Parkinson's disease midbrain neurons, in regulating both mitophagy and mitochondrial biogenesis. We will utilize differentiated neuroblastoma cells, primary embryonic mouse neurons and in vivo mouse models to study the mechanism(s) leading to the observed decreases in mitochondrial content and function, study the role of phosphorylation in regulating biogenesis, and determine the neuroprotective potential for strategies to modulate mitochondrial content in toxin and dominant genetic models of Parkinson's disease.

Public Health Relevance

Mitochondria represent the primary source of energy within brain cells (neurons). While removing damaged mitochondria can be beneficial, excessive loss of mitochondria also contributes to neurodegeneration in several models of Parkinson's disease. We will determine why these injuries reduce mitochondrial content, and whether enhancing the ability of neuronal cells to rebuild new mitochondria promotes beneficial effects of mitochondrial recycling.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026389-07
Application #
8646831
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Wise, Bradley C
Project Start
2013-05-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
$314,931
Indirect Cost
$109,931
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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