PINK1 regulation of neuronal and mitochondrial homeostasis PROJECT SUMMARY. Mutations in PTEN-induced kinase 1 (PINK1) cause familial autosomal recessive parkinsonism. As PINK1 plays a neuroprotective role in a wide range of genetic and toxin-induced Parkinson's disease (PD) models, studying its function in neurons may offer particular insights into potential therapeutic strategies. In the prior project period, we found that endogenous PINK1 exists in mitochondrial and cytosolic compartments. Moreover, these pools of PINK1 played divergent roles in regulating mitochondrial fission-fusion, mitophagy, calcium homeostasis and dendritic morphogenesis. Using primary neurons, differentiated neuronal cell lines and Pink1 knockout and control mice, the current proposal focuses on studying mechanisms by which PINK1 regulates neuron differentiation and the maintenance of extended axo-dendritic arbors. Based on preliminary data, we hypothesize that PINK1 interacts with cytosolic targets to regulate neuron differentiation and dendritic spine formation. We will study the role of novel PINK1-interacting proteins in regulating dendritogenesis and mitochondrial transport into neurites. The impact of PD-related mutations will be analyzed, and the neuroprotective potential of upregulating downstream pathways tested using Pink1-/- mice. Obtaining a better understanding of neuron-specialized functions of PINK1 in regulating dendritogenesis and compartmentalized mitochondrial content will yield valuable insights towards future strategies to reduce neuron dysfunction in PD.
. Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) contribute to a recessive form of Parkinson's disease. In this proposal, we will focus on mechanisms by which PINK1 promotes the elaboration and maintenance of an extended network of thin cellular extensions that function like communication cables in the brain. We will examine the role of proteins that we discovered can interact with PINK1, and how parkinsonian mutations in PINK1 affect these interactions. Completion of this study will enhance understanding of mitochondrial and cytosolic mechanisms by which PINK1 regulates these structural elements, which are essential for brain cell health and function. This in turn may help identify new strategies 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|
Showing the most recent 10 out of 34 publications