Charleen T. Chu, Associate Professor
PhD, Duke University Medical Center, 1993
MD, Duke University Medical Center, 1994
Email: ctc4@pitt.edu
Home Page: http://path.upmc.edu/people/faculty/chu.html
Dr. Chu's laboratory focuses on cellular and molecular mechanisms of neurodegeneration in Parkinson disease. Molecular and biochemical studies in cell culture and mouse models are integrated with pathologic studies of diseased human brain tissues. Major themes in the laboratory include redox cell signaling and autophagy in neurite injury, regeneration and cell death. The unifying hypothesis is that oxidative stress disrupts adaptive signaling, transcriptional and degradative responses to injury, tipping the balance to favor neuronal cell death. Our data indicate that that inappropriate regulation of signaling proteins and macroautophagy may result in conversion of these cellular responses into detrimental pathways that promote further injury.
Oxidative regulation of neurodegenerative and neuroprotective cell signaling. One major focus of the laboratory is delineating effects of reactive oxygen species upon intracellular signaling cascades. We have found that the parkinsonian neurotoxin 6-OHDA perturbs mitogen activated protein kinase (MAPK) and cAMP response element binding protein (CREB) signaling in neuronal cell lines, resulting in cytoplasmic diversion of nuclear proteins and decreased neuroprotective transcription. Moreover, examination of human Parkinson disease brain tissues reveal granular cytoplasmic aggregates of phospho-ERK and phospho-CREB within mitochondria, suggesting that altered kinase trafficking contributes to parkinsonian neurodegeneration.
Mitochondrial biology and kinases linked to familial Parkinson's disease. We are also interested in delineating common pathways of injury affected by both genetic and environmental/toxic causes of parkinsonian neurodegeneration. These include mitochondrial oxidative stress and altered organelle/vesicle trafficking. Our cell culture and mouse model work implicated mitochondrial ROS in activation of MAPK signaling pathways. Two kinases implicated in familial Parkinson disease include the mitochondrial PTEN-induced kinase 1 (PINK1) and the leucine rich repeat kinase 2 (LRRK2), which has Rab GTPase-like and MAPKKK-like domains.
Autophagy in neurite injury and cell death. Although evidence for classic apoptosis is controversial for neurodegenerative diseases, neurons do undergo other forms of regulated cell death. We observed increased autophagy during death-inducing injury to neuronal cell lines and primary dopaminergic neurons. Autophagy is also increased in human Parkinson disease neurons. While there has been growing interest in "autophagic programmed cell death," the potential beneficial or detrimental roles of autophagy in neurite retraction and cell death responses to parkinsonian injury remain undefined. The regulation of mitochondrial autophagy forms an area of special interest.
Trainees in the laboratory will utilize biochemical and molecular techniques as applied to primary neuronal cultures and transfected cell lines, diseased human tissues, or parkinsonian toxins applied to transgenic mice. Techniques in cell death, post-translational protein modifications, molecular biology and quantitative immunohistochemistry/immunofluorescence are central. Training opportunities in protein purification, spectrophotometric enzyme assays, confocal microscopy, and stereotactic brain injections are also available.
Recent Publication
JH Zhu, C Horbinski, F Guo, S Watkins, Y Uchiyama & CT Chu (2007). Regulation of autophagy by extracellular signal regulated protein kinases during 1-methyl-4-phenylpyridinium injury. Am J. Pathol, 170: 75-86.
EM Chalovich, JH Zhu, J Caltagarone, R Bowser & CT Chu (2006) Functional repression of cAMP response element in 6-hydroxydopamine-treated neuronal cells. J. Biol. Chem, 281: 17870-17881.
CT Chu, JH Zhu, G Cao, A Signore, S Wang & J Chen (2005) Apoptosis-inducing factor mediates caspase-independent 1-methyl-4-phenylpyridinium toxicity in dopaminergic cells. J. Neurochem, 94: 1685-1695.
J Callio, TD Oury & CT Chu (2005) Manganese superoxide dismutase protects against 6-hydroxydopamine injury in mouse brains. J Biol Chem, 280:18536-18542.
JH Zhu, F Guo, J Shelburne, S Watkins & CT Chu. (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol, 13: 473-481.
Reviews
CT Chu. (2006) Autophagic stress in neuronal injury and disease. J Neuropath Exp Neurol, 65: 423-432.
C Horbinski & CT Chu (2005) Kinase signaling cascades in the mitochondrion: A matter of life or death. Free Rad Biol Med. 38: 2-11.
CT Chu, DJ Levinthal, SM Kulich, EM Chalovich, and DB DeFranco (2004) Oxidative neuronal injury: The dark side of ERK 1/2. Eur J Biochem, 271: 2060-2066.
