Parkinson's disease (PD), caused by selective loss of dopaminergic (DA) neurons in the substantia nigra pars compacta, is the most common movement disorder affecting 1% of the population over the age 60 with no cure or effective treatment. Although the etiology of PD remains unknown, converging evidence from genetic and toxin models points to dysregulation of mitochondrial remodeling and turnover as prominent cellular defects in PD pathophysiology. We recently reported that hucp2 expression in Drosophila DA neurons protects flies against rotenone-induced DA neuron death and head dopamine depletion. We have expanded our toxin model and demonstrated hUCP2 protective effect against MPP+-induced DA neuron degeneration. To begin to understand the protective mechanisms, we considered the bioenergetic consequences of mitochondrial uncoupling and postulated AMP activated protein kinase (AMPK) as a downstream effector of hUCP2. In supporting this idea, we detected phosphorylated AMPK? indicative of its activation when hucp2 expression is induced in Drosophila S2R+ cells. Consistent with our genetic interaction study revealing functional cooperation between hUCP2 and mitochondrial fusion molecules, our current results suggest hUCP2 neuroprotective effect requires mitochondrial fusion. Furthermore, increased autophagic activity is associated with hucp2 expression in brain DA neurons. Additional support for our proposed hUCP2-AMPK axis are results showing that toxin-induced mitochondrial fragmentation is attenuated in hucp2 or AMPK expressing primary DA neurons and AMPK protective effect against toxin-induced neuron loss is associated with less accumulation of the autophagy receptor Ref(2)P. Taken together, those preliminary results led us to hypothesize that activation of AMPK as the result of hucp2 expression promotes mitochondrial fusion and autophagy to enhance mitochondrial health and survival of DA neurons. To test our hypothesis, we will determine i) whether AMPK is a downstream effector of hUCP2 in regulating mitochondrial fusion/fission in DA neurons, ii) whether AMPK stimulates autophagic activity and mitochondrial turnover in DA neurons exposed to toxin and iii) whether mitochondrial fusion and autophagy are critical components in hUCP2-AMPK mediated DA neuron survival against toxin.

Public Health Relevance

Parkinson's disease is the second most prevalent neurodegenerative disease affecting 1% of the population over the age 60 with no cure or effective treatment. In an effort to identify potential therapeutic targets for alternative treatmet strategies, we demonstrated human uncoupling protein 2 (hUCP2) protective effect in dopaminergic neurons against toxin. To delineate the underlying mechanisms, we will test our hypothesis that activation of the intracellular energy sensor, AMP-activated protein kinase as the result of hucp2 expression plays a central role in coordinating mitochondrial quality control pathways and cell survival in dopaminergic neurons.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56NS082784-01A1
Application #
8739993
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Sutherland, Margaret L
Project Start
2013-09-30
Project End
2014-08-31
Budget Start
2013-09-30
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$323,007
Indirect Cost
$73,007
Name
University of Connecticut
Department
Other Health Professions
Type
Schools of Earth Sciences/Natur
DUNS #
614209054
City
Storrs-Mansfield
State
CT
Country
United States
Zip Code
06269