In recent years, mutations in PTEN-induced kinase 1 (PINK1) have been associated with autosomal recessive Parkinsonism. Early studies have uniformly shown a neuroprotective role for PINK1, indicating that studying this familial form of PD may offer valuable insights into potential therapeutic strategies. Dysregulation of mitochondria and autophagy are both centrally implicated in toxin, genetic and environmental approaches to modeling PD. Our preliminary data implicate PINK1 in the upstream regulation of autophagy and in maintenance of mitochondrial interconnectivity, neurite health and synaptic function. Using differentiated neuronal cell lines and primary neuron cultures from control and PINK1 knockout mice, we will determine mechanisms by which PINK1 protects from toxin and genetic PD models, focusing on: 1) the role of subcellular localization in PINK1-mediated neuroprotection, 2) mechanisms regulating PINK1 localization, and 3) identification and characterization of downstream components of the PINK1 signaling pathway, using both candidate and nonbiased proteomic approaches. Achieving the goals of this project to obtain a better understanding of PINK1 regulation, subcellular compartmentalization and downstream pathways will provide insight into new therapeutic strategies to reduce neuronal dysfunction and cell death in PD.
. 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 identification of new therapeutic targets to prevent or slow neurodegeneration in Parkinson's and related diseases.
|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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