Dopaminergic (DA) neurons are sensitive to oxidative insults and degenerate in age-related neurodegenerative diseases. A morphologic form of regulated cell death characterized by prominent autophagic vacuoles (AVs) has been identified in neurons. Autophagy is normally a highly regulated process sequestering cytoplasmic components for lysosomal degradation. However, dysregulated or excessive autophagy can be harmful to cells, producing a condition that can be conceptualized as """"""""autophagic stress."""""""" Although AVs are observed in degenerating DA neurons in Parkinson disease and its in vitro and in vivo models, the role of autophagy in DA neuronal injury remains to be elucidated. Our studies indicate that oxidative neurotoxins elicit increased mitochondrial autophagy in DA neurons. Moreover, the regulation of this injury-induced autophagy is different from that of nutrient-deprivation systems. This proposal investigates the hypotheses that: autophagy contributes to neurite retraction and cell death in injured DA neurons, and that reactive oxygen species and MARK signals regulate injury-induced autophagy. We will use the complex I inhibitor MPP+ to produce mitochondria-targeted injury, and the redox cycling 6- hydroxydopamine to model generalized oxidative stress, comparing acute and chronic treatments. A combination of molecular, biochemical, live cell imaging and transgenic approaches will be applied to DA cell lines, primary midbrain cultures and mice to determine the role of autophagy in DA neurite retraction and cell death, and to study MAPK and oxidative phospholipid signals involved in its regulation. Completion of these studies will yield important insights into mechanisms by which autophagic responses regulate DA neurite degeneration and cell death during oxidative neuronal injuries. Relevance: Mitchondrial impairment and autophagic stress are prominent features of Parkinson/Lewy body disease. In contrast to physiologic conditions, inducing autophagy in the presence of dysregulating pathologic forces may promote cell death. A better understanding of mechanisms that contribute to autophagic stress will help focus future research efforts to restore balance to the system. Thus, studying the role and regulation of autophagic responses in oxidatively-injured neurons may enhance development of novel therapies applicable to age-related neurodegenerative diseases and other brain disorders involving oxidative stress. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG026389-02
Application #
7470602
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Wise, Bradley C
Project Start
2007-08-01
Project End
2012-04-30
Budget Start
2008-05-01
Budget End
2009-04-30
Support Year
2
Fiscal Year
2008
Total Cost
$298,337
Indirect Cost
Name
University of Pittsburgh
Department
Pathology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Verma, Manish; Wills, Zachary; Chu, Charleen T (2018) Excitatory Dendritic Mitochondrial Calcium Toxicity: Implications for Parkinson's and Other Neurodegenerative Diseases. Front Neurosci 12:523
Chu, Charleen T (2018) Multiple pathways for mitophagy: A neurodegenerative conundrum for Parkinson's disease. Neurosci Lett :
Kang, Inhae; Chu, Charleen T; Kaufman, Brett A (2018) The mitochondrial transcription factor TFAM in neurodegeneration: emerging evidence and mechanisms. FEBS Lett 592:793-811
Das Banerjee, Tania; Dagda, Raul Y; Dagda, Marisela et al. (2017) PINK1 regulates mitochondrial trafficking in dendrites of cortical neurons through mitochondrial PKA. J Neurochem 142:545-559
Gusdon, Aaron M; Callio, Jason; Distefano, Giovanna et al. (2017) Exercise increases mitochondrial complex I activity and DRP1 expression in the brains of aged mice. Exp Gerontol 90:1-13
Verma, Manish; Callio, Jason; Otero, P Anthony et al. (2017) Mitochondrial Calcium Dysregulation Contributes to Dendrite Degeneration Mediated by PD/LBD-Associated LRRK2 Mutants. J Neurosci 37:11151-11165
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Banerjee, Kalpita; Munshi, Soumyabrata; Xu, Hui et al. (2016) Mild mitochondrial metabolic deficits by ?-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer's disease. Neurochem Int 96:32-45
Kagan, V E; Jiang, J; Huang, Z et al. (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Differ 23:1140-51
Di Maio, Roberto; Barrett, Paul J; Hoffman, Eric K et al. (2016) ?-Synuclein binds to TOM20 and inhibits mitochondrial protein import in Parkinson's disease. Sci Transl Med 8:342ra78

Showing the most recent 10 out of 57 publications