Charleen T. Chu, MD, PhD
Professor of Pathology
A. Julio Martinez Chair in Neuropathology
Dr. Chu is Director of the Ophthalmic Pathology Service in the Division of Neuropathology and Co-Director of the Pathologist Investigator Residency/Research Training Program. As principal investigator, she directs a basic research program focused on mitochondrial pathobiology and Parkinson's disease, and is training faculty for the Pathology and Neuroscience Graduate programs, the MSTP and the PSTP. She is also a member of the McGowan Institute for Regenerative Medicine and the Mitochondria, Metabolism and Disease Working Group.
S701.1 Scaife Hall
3550 Terrace Street
Pittsburgh, PA 15261
Office Telephone: 412-383-5379
Clinical ExpertiseDr. Chu is director of the ophthalmic pathology service. For information on submitting specimens, visit the Eye Consults page. For information on training in academic neuropathology or ophthalmic pathology, visit the Neuropathology website.
Research InterestsDr. Chu's Lab Home Page
2010 Carnegie Science Awards Profile of Dr. Chu's Research
Cell Biology of Parkinson's Disease: Mitochondrial Quality Control, Kinase Signaling & Autophagy
Dr. Chu's research focuses on mechanisms of neurodegeneration and neuroprotection in Parkinson's and related neurodegenerative diseases. A major focus is delineating why adaptive cellular mechanisms fail to protect neurons. Molecular and biochemical studies in cell culture and mouse models are integrated with studies of diseased human brain tissues. Recent focus has shifted from cell death to mechanisms of mitochondrial quality control and neuritic/synaptic dysfunction at potentially reversible stages.
Work in the Chu laboratory indicates that pathogenic mechanisms related to five models of PD converge on dysregulation of mitochondrial kinase signaling and turnover by autophagy, the process by which cells sequester, degrade and recycle organelles. These include 6-OHDA and MPP+, two parkinsonian neurotoxins, and genetic models based on mutations in PTEN-induced kinase 1 (PINK1), a mitochondrial kinase, the leucine-rich repeat kinase 2 (LRRK 2), a membrane associated multidomain kinase, and ATP13A2, a lysosomal transporter by homology. Analysis of Parkinson disease and Lewy body dementia brain tissues reveal similar alterations in the localization and trafficking of phosphorylated kinases and transcription factors, associated with mitochondrial autophagy, in susceptible populations of neurons early in the disease process.
While there has been growing interest in therapeutic manipulation of autophagy, the potential beneficial or detrimental roles of autophagy in neuronal responses to parkinsonian injury remain undefined. Our work has led to the concept of "autophagic stress," in which imbalanced or excessive induction of autophagy contributes to neuronal dysfunction. For example, ERK1/2 activation, as observed in degenerating human PD neurons and in the chronic MPP+ model, may be harmful to neurons because it activates mitophagy and phosphorylates TFAM at S177 to suppress mitochondrial transcription. We found that PINK1 is essential for maintaining well-functioning mitochondrial networks. Moreover, processed PINK1 that is released from healthy mitochondria serves as a signal of mitochondrial health, suppressing autophagy while engaging pathways that activate pro-differentiation pathways in neurons. Using mass spectrometry, we identified a novel phosphorylation site on the autophagy protein LC3, which protects against neurite degeneration caused by MPP+ or mutant LRRK2. We discovered a novel cargo recognition signal for mitophagy in neurons, which involves exposure of cardiolipin to the surface of damaged mitochondria, where it binds LC3. Furthermore, mutant LRRK2 causes excitotoxic calcium dysregulation in dendrites, which triggers mitochondrial loss and autophagic dendritic degeneration. Current efforts are focused on delineating downstream signaling complexes or targets that regulate mitophagy, calcium homeostasis and mitochondrial function.
TechniquesProtein biochemistry, molecular cell biology, mass spectrometry and phospho-proteomics, quantitative RT-PCR, immunochemistry, multi-label confocal microscopy, electron microscopy, stereotactic brain injections, RNA interference.
Dr. Chu is a member of the Graduate Programs of Cellular and Molecular Pathology (CMP) and Center for Neuroscience (CNUP), the Medical Scientist Training Program (MSTP) and the Physician Scientist Training Program (PSTP). She is committed to career development of pre-doctoral, post-doctoral and physician-scientist trainees, developing and directing for 10 years a MSTP Professional Development course focused on grant writing and peer-review, which is now emulated by other MSTP and graduate programs nationwide. She is founding co-director for the Pathologist Investigator Residency/Research Training Program. This "PI-training track" is designed to develop the next generation of physician-scientist leaders, independently-funded Academic Pathologists pursuing combined research and diagnostic careers.
Selected PublicationsView Dr. Chu's recent publications on PubMed
View Dr. Chu's previous publications on PubMed
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), In press. http://goo.gl/B4WvCo
KZQ Wang, J Zhu, RK Dagda, G Uechi, SJ Cherra III, AM Gusdon, M Balasubramani & http://goo.gl/5vboHx. (2014) ERK-mediated phosphorylation of TFAM downregulates mitochondrial transcription. Mitochondrion, in press. http://goo.gl/5vboHx.
RK Dagda, I Pien, R Wang, J Zhu, KZQ Wang, J Callio, TD Banerjee, RY Dagda & http://goo.gl/5vboHx (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 Bay?r & VE Kagan (2013) Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells. Nature Cell Biol 15:1197-1205.
SJ Cherra III, E Steer, AM Gusdon, K Kiselyov & CT Chu. (2013) Mutant LRRK2 elicits calcium imbalance and depletion of dendritic mitochondria in neurons. Am J Pathol, 182: 474-484.
RK Dagda, A Gusdon, I Pien, S Strack, S Green, B Van Houten, SJ Cherra III & CT Chu. (2011) Mitochondrially localized PKA reverses mitochondrial pathology and dysfunction in a cellular model of Parkinson's disease. Cell Death Differ 18: 1914-1923.
SJ 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.
RK Dagda, SJ Cherra III, SM Kulich, A Tandon, D Park & CT Chu. (2009) Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 284: 13843-13855.
Selected Books, Reviews, and Clinical AritclesZ Yue & CT Chu, Editors. (2012) Autophagy of the Nervous System: Cellular Self-Digestion in Neurons and Neurological Diseases. World Scientific Press, Singapore, 2012. 440 pp. ISBN - 978-981-4350-44-0. Available at World Scientific and Amazon.
E Oczypok, TD Oury & CT Chu. (2013) It's a cell eat cell world: Autophagy and phagocytosis. Am J Pathol 182: 612-622.
JE Knickelbein, J Kovarik, DK Dhaliwal & CT Chu. (2013) Acanthamoeba keratitis: A clinico-pathologic case report and review of the literature. Human Pathol, 44: 918-922.
J Zhu, KZQ Wang & CT Chu. (2013) After the banquet: Mitochondrial biogenesis, mitophagy and cell survival. Autophagy 9: 1663-76.
M Verma, EK Steer & CT Chu. (2013) ERKed by LRRK2: A cell biological perspective on hereditary and sporadic Parkinson's disease. Biochim Biophys Acta (Molecular Basis of Disease) In press.