Mutations in PTEN-induced kinase 1 (PINK1) are associated with autosomal recessive parkinsonism. Early studies have uniformly shown a neuroprotective role for PINK1, indicating that studying this familial form of Parkinson's Disease (PD) may offer valuable insights into potential therapeutic strategies. Dysregulation of mitochondria and autophagy are each centrally implicated in toxin, genetic and environmental approaches to modeling PD. Using knockdown and targeted expression systems, we identified a set of mitochondrial, autophagic and neurite-stabilizing functions downstream of PINK1. Using differentiated neuronal cell lines and primary neurons harvested from control and PINK1 knockout mice, we will now determine mechanisms by which PINK1 protects in toxin and genetic PD models, focusing on: 1) the role of subcellular localization in PINK1 regulation of mitochondrial and neurite stability, 2) the effects of PD-linked mutations on mechanisms that regulate these two facets of PINK1 neuroprotection, and 3) continued characterization of potential PINK1 pathway mediators, using candidate and nonbiased proteomic approaches. Achieving the goals of this project to obtain a better understanding of PINK1 regulation of autophagy and mitochondria will provide insight into new therapeutic strategies to reduce neuronal dysfunction in PD.

Public Health Relevance

Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) contribute to a recessive form of Parkinson's disease. Completion of this study will enhance understanding of mechanisms by which PINK1 confers protection in models of parkinsonian injury, and the subcellular regulation of its functions. Developing this basic knowledge represents a necessary first step towards continued identification of potential therapeutic targets to prevent or slow neurodegeneration in Parkinson's and related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS065789-02
Application #
8269861
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
2010-07-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$331,406
Indirect Cost
$112,656
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

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