Charleen T. Chu, MD, PhD

  • Professor, Pathology

Phone

412-383-5379

E-mail

ctc4@pitt.edu

Personal Website

website link

Education & Training

MD, Duke University (1994)
PhD, Duke University (1993)

Campus Address

Scaife Hall, S-701

One-Line Research Description

Cell signaling, dendritic morphogenesis and autophagy/mitophagy in neurodegenerative diseases

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.

Representative Publications

Verma, Z Wills & CT Chu. (2018) Excitatory dendritic mitochondrial calcium toxicity: Implications for Parkinson’s and other neurodegenerative diseases. Front Neurosci 12: 523 (12 pages). PMID:30116173; PMCID:PMC6083050; DOI:10.3389/fnins.2018.00523EK
M Verma, J Callio, PA Otero, I Sekler, ZP Wills & CT Chu. (2017) Mitochondrial calcium dysregulation contributes to dendrite degeneration mediated by PD/LBD-associated LRRK2 mutants. J. Neurosci37: 11151-11165. 

Cherra III, SM Kulich, G Uechi, M Balasubramani, J Mountzouris, BW Day & CT Chu. (2010) Regulation of the autophagy protein LC3 by phosphorylation. J. Cell. Biol. 190: 533-539. doi: 10.1083/jcb.201002108. PMID:20713600; PMCID: PMC2928022F1000

AM Gusdon, J Callio, G DiStefano, RM O’Doherty, B Goodpaster, PM Coen & CT Chu. (2017) Exercise Increases Mitochondrial Complex I Activity and DRP1 Expression in the Brains of Aged Mice. Exp Gerontol 90: 1-13.  
KZQ Wang, J Zhu, RK Dagda, G Uechi, SJ Cherra III, AM Gusdon, M Balasubramani & CT Chu. (2014) ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription. Mitochondrion, 17: 132-140.

Wang*, E Steer*, PA Otero*, NW Bateman, MH Cheng, AL Scott, C Wu, I Bahar, YT Shih, YP Hsueh & CT Chu. (2018) PINK1 interacts with VCP/p97 and activates PKA to promote NSFL1C/p47 phosphorylation and dendritic arborization in neurons. eNeuro, 5: ENEURO.0466-18.2018, 1-16.*co-first authors, equal contributions. PMCID:PMC6377406

VP Patel & CT Chu. (2014) Decreased SIRT2 activity leads to altered microtubule dynamics in oxidatively-stressed neuronal cells: Implications for Parkinson’s disease. Exp. Neurol. 257: 170-181.
 
E Plowey, JW Johnson, D Eisenberg, NM Valentino, YJ Liu & CT Chu. (2014) Mutant LRRK2 overexpression in cultured cortical neurons elicits glutamatergic synapse activity and excitotoxic neurite degeneration. Biochim. Biophys. Acta (Molecular Basis of Disease) 1842: 1596-1603.  
 
RK Dagda, I Pien, R Wang, J Zhu, KZQ Wang, J Callio, TD Banerjee, RY Dagda & CT Chu (2014) Beyond the mitochondrion: cytosolic PINK1 remodels dendrites through Protein Kinase A. J Neurochem 128:  864-877.
 
CT Chu*, J Ji, RK Dagda, JF Jiang, YY Tyurina, AA Kapralov, VA Tyurin, N Yanamala, IH Shrivastava, D Mohammadyani, KZQ Wang, J Zhu, J Klein-Seetharaman, K Balasubramanian, AA Amoscato, G Borisenko, Z Huang, AM Gusdon, A Cheikhi, EK Steer, R Wang, C Baty, S Watkins, I Bahar, H Bayır* & VE Kagan* (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nature Cell Biol15:1197-1205.

Zhu, A Gusdon, H Cimen, B Van Houten, E Koc & CT Chu. (2012) Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity. Cell Death Dis 3: e312, 1-10. doi: 10.1038/cddis.2012.46. PMCID: PMC3366080SJ

Chu. (2019) Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases. Neurobiol Dis 122: 23-34.PMID:30030024; DOI: 10.1016/j.nbd.2018.07.015M

 

Selected Review Articles

CT Chu. (2018) Mechanisms of selective autophagy and mitophagy: Implications for neurodegenerative diseases. Neurobiol Dis in press. DOI: 10.1016/j.nbd.2018.07.015

M Verma, Z Wills & CT Chu. (2018) Excitatory dendritic mitochondrial calcium toxicity: Implications for Parkinson’s and other neurodegenerative diseases. Front Neurosci 12: 523 (12 pages).

I Kang, CT Chu, BA Kaufman. (2018) The mitochondrial transcription factor TFAM in neurodegeneration: Emerging evidence and mechanisms. FEBS Lett592(5):793-811. 

EK Steer, MK Dail & CT Chu. (2015) Beyond mitophagy: cytosolic PINK1 as a messenger of mitochondrial health. Antioxid Redox Signal 22:  1047-1059. 

Link to a more complete list of Dr. Chu's recent publications