Charleen T. Chu, MD, PhD

Professor, Pathology

Contact

Scaife Hall, S-701
412-383-5379
F: 412-624-5610
ctc4@pitt.edu

CV


Website >

Education

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

Focus

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

Research Summary

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.

Summer Undergraduate Research Program

Yes

Publications

Selected Publications
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. 
 
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. Mitochondrion17: 132-140.
 
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.
 

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