Cell signaling, mitochondria and autophagy regulation in genetic models of Parkinson's disease.
Dr. Chu's research explores the interplay between kinase signaling, mitochondrial function and pathological neuritic/synaptic remodeling in toxin and genetic models of Parkinson's disease.
Reactive oxygen species and mitochondrial pathobiology have been implicated in the pathogenesis of neurotoxin and genetic models of Parkinson's disease (PD). Although the extracellular signal regulated protein kinases (ERK) are activated by growth factors, redox activation of this signaling pathway promotes neuronal cell death. Our studies in primary neurons, neuronal cell lines and diseased human brain tissues, suggest that deranged trafficking and transport of signaling proteins contributes to mitochondrial dysfunction, neurite degeneration and cell death. Our long-term goals are to understand mechanisms by which adaptive responses are dysregulated during acute and chronic neurodegenerative stresses in order to develop neuroprotective or regenerative therapies.
Kinases that are mutated in familial forms of Parkinson's disease, LRRK2 and PINK1, affect important cellular pathways governing mitochondrial quality control and maintenance of differentiated neuronal processes, in part through modulation of autophagy. A third gene encoding a lysosomal ATPase also affects mitochondrial function. Current areas of emphasis include combined proteomic and molecular imaging approaches to defining mitochondrial and autophagy regulatory targets that act downstream of LRRK2, PINK1 and ATP13A2 mutations to promote neurodegenerative pathology and inhibit reparative biogenesis. Recent advances include the identification of a novel phosphorylation site of the autophagy protein MAP1-LC3, which mediates neuroprotective effects of PKA, and possibly PINK1, in the mutant LRRK2 and MPP+ models.
Trainees in the laboratory will be exposed to biochemical, immunochemical, image analysis, and molecular techniques as applied to cell culture and transgenic/knockout mouse models. In addition, we conduct neuropathologic and biochemical studies of diseased tissues from patients with PD and Lewy body dementia (LBD). The ability to test predictions in post-mortem human neurodegenerative disease brain samples has already translated to new directions for our experimental work.
S Ravi, KA Pena, CT Chu, K Kiselyov. (2016) Biphasic regulation of lysosomal exocytosis by oxidative stress. Cell Calcium, in press.
R Di Maio, PJ Barrett, EK Hoffman, CW Barrett, A Zharikov, A Borah, X Hu, J McCoy, CT Chu, EA Burton, TG Hastings, JT Greenamyre. (2016) a-Synuclein binds TOM20 and inhibits mitochondrial protein import in Parkinson’s disease. Sci Transl Med 8: 342ra78.
NQ Richards, JK Kofler, CT Chu, ST Stefko (2016) Intraocular synovial sarcoma. Retin Cases Brief Rep In press.
K Banerjee, S Munshi, H Xu, DE Frank, HL Chen, CT Chu, J Yang, S Cho, VE Kagan, TT Denton, YY Tyurina, JF Jiang, GE Gibson. (2016) Mild mitochondrial metabolic deficits by a-ketoglutarate dehydrogenase inhibition cause prominent changes in intracellular autophagic signaling: Potential role in the pathobiology of Alzheimer’s disease. Neurochem Int 96:32-45.
VE Kagan, J Jiang, Z Huang, YY Tyrurina, C Desbourdes, C Cottet-Rousselle, H Dar, M Verma, VA Tyurin, AA Kapralov, A Cheikhi, G Mao, D Stolz, CM S. Croix, S Watkins, Z Shen, Y , ML Greenberg, M Tokarska-Schlattner, M Boissan, M-L Lacombe, RM Epand, CT Chu, R Mallampalli, H Bayır, U Schlattner. (2016) NDPK-D (NM23-H4)-dependent externalization of cardiolipin during elimination of depolarized mitochondria. Cell Death Differ 23: 1140-1151.
M Kostic, MHR Ludtmann, H Bading, M Hershfinkel, E Steer, CT Chu, AY Abramov & I Sekler. (2015) PKA phosphorylation of NCLX reverses mitochondrial calcium overload and depolarization, promoting survival of PINK1-deficient dopaminergic neurons. Cell Reports 13: 376-386. http://www.sciencedirect.com/science/article/pii/S2211124715009924
AK Au, Y Chen, L Du, CM Smith, MD Manole, SA Baltagi, CT Chu, RK Aneja, H Bayır, PM Kochanek & RSB Clark. (2015) Ischemia-induced autophagy contributes to neurodegeneration in cerebellar Purkinje cells in the developing brain and in primary cortical neurons in vitro. Biochim. Biophys. Acta (Molecular Basis of Disease) 1852: 1902-1911. doi:10.1016/j.bbadis.2015.06.007
AM Gusdon, F Fang, J Chen, CE Mathews, W Li, CT Chu, JQ Ding & SD Chen (2015) Association of the mt-ND2 5178A/C polymorphism with Parkinson’s disease. Neurosci Lett 587: 98-101. PMID: 25511548
M Bueno, M Mosher, C Kamga, C Corey, D Stolz, C StCroix, M Rojas, S Shiva, CT Chu & AL Mora. (2015) PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest 125: 521-538. PMCID: PMC4319413
Link to a more complete list of Dr. Chu's recent publications