John Feng, Ph.D.
Mt. Sinai Scholar
Assistant Professor, Department of Pharmacology, School of Medicine
Assistant Professor, Department of Electronic Engineering and Computer Science, School of Engineering
Case Western Reserve University
Phone: (216) 368-3751
Fax: (216) 368-1300
E-mail: john.feng@case.edu
W309A Wood Building
Research
The research of my lab focuses on dopamine neurotransmission and dopamine neurotransmisson related Parkinson’s Disease. I use mutiple models, C. elegans, human cell culture and mice, and multiple-disciplinary approaches, optogenetics, calcium imaging, pharmacology, biochemistry, cell biology and behaviral analysis.
Dopamine neurotransmission
Dopamine is an important neurotransmitter that mediates motor, reward, motivation and learning in humans. For example, dopamine neurotransmission mediates nicotine depence in human. In human nervous system, dopamine acts through G protein-coupled receptors (GRCRs). However, the signaling pathways of these dopamine receptors (DOPs) are poorly understood. Because the G protein-coupled signaling systems are highly conserved across phylogeny, we use genetic model organism, C. elegans, to identify the signaling pathways. To do so, we first developped an optogenetic approach (Cao, P., et al, FASEB J.) to control G protein signaling in freely behaving C. elegans at spatialtemporal presion. We are now using this optogenetic approach to identify signal pathways of G protein, and examining how DOPs act through these identified pathways to regulate neuromotor behavior.
Dopaminergic neurodegeneration
Degeneration of dompainergic neurons leads to Parkinson’s Disease featured by the loss of motor capalcity. Leucine-rich repeat kinase 2 (LRRK2) is the leading PD familial gene and a promising therapeutic target. Multiple biologic mechanisms of LRRK2 have been suggested, but the pathogenic contribution of LRRK2 to PD still remains an enigma. To develop potent and specific therapies, it is critical to determine the role of LRRK2 in cell viability.
We generate hypothesis regarding dopaminergic neurodegeneration using C. elegans, validate the hypothesis using human cell lines and test the physiological relavance using mice.
LRRK2 co-localizes with Lewy bodies and associates with the endoplasmic reticulum (ER) in PD affected neurons of patients, suggesting an interaction between LRRK2 and ER stress in pathogenesis. However, the functional link between LRRK2 and ER stress is poorly understood. Recently, we reported that the LRRK2/p38 signaling prevented neurotoxin-mediated human neuroblastoma cell death by supporting the pro-survival program of ER stress, establishing the functional connection between LRRK2 and ER stress in cell fate decision for the first time (Yuan, Y., et al, PLoS ONE). We are now continuing to study how LRRK2 regulates ER stress to promote the death of cells under stress.
Related publications (3-11 published at Case)
Feng, Z., Li, W., Ward, A., Piggott, B.J., Larkspur, E., Sternberg, P.W., and Xu, X.Z.S. (2006) A C. elegans model of nicotine-dependent behavior: regulation by TRP family channels. Cell 127, 621-633. (PMID: 17081982)
Ward, A., Liu, J., Feng, Z. and Xu, X.Z.S. (2008) Light-sensitive neurons and channels mediate phototaxis in C. elegans. Nat. Neurosci. 2008 July 6 | doi:10.1038/nn.2155,1-7. (PMCID: PMC2652401)
Hsu, A-L*, Feng, Z.*, Hsieh, M-Y, and Xu, X.Z.S. (2008) Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans. (* indicating co-first authors)) Neurobiol. of Aging 2008 Feb 8 | doi:10.1016/j.neurobiolaging. (PMCID: PMC2747634)
Cao, P., Yuan, Y., Pehek, E.A., Moise, A.R., Huang, Y., Palczewski, K., and Feng, Z. (2010) Alpha-synuclein disrupted dopamine homeostasis leads to dopaminergic neuron degeneration in Caenorhabditis elegans. PLoS One 2010 Feb 19; 5 (2):e312. (PMCID: PMC2824852)
Li, W., Kang, L., Piggott, B.J., Feng, Z. and Xu X.Z.S. (2011) The neural circuits and sensory channels mediating harsh touch sensation in Caenorhabditis elegans. Nat. Commun. 2:315 (PMCID: PMC3098610)
Zhang, S., Jin, W., Huang, Y., Su, W., Yang, J., and Feng, Z. (2011) Profiling a Caenorhabditis elegans behavioral parametric dataset with a supervised K-means clustering algorithm identifies genetic networks regulating locomotion. J. Neurosci. Meth.: doi:10.1016/j.physletb.2003.10.071. (PMCID: PMC3084513)
Yuan, Y., Cao, P., Smith, M.A., Kramp, K., Huang, Y., Hisamoto, N., Matsumoto, K., Hatzoglou, M., Jin, H. and Feng, Z. (2011) Dysregulated LRRK2 Signaling in response to endoplasmic reticulum stress leads to dopaminergic neuron degeneration in C. elegans. PLoS One2011 Aug 3; 6 (8):e22354. (PMCID: PMC3153934)
Piggott, B.J.*, Liu, J.*, Feng, Z. *, Wescott, S.A., and Xu, X.Z.S. (*: co-first author) (2011) The neural circuits and synaptic mechanisms underlying motor initiation in C. elegans. Cell 147(4):922-3. (PMID: 22078887)
Salom, D., Cao, P., Sun, W., Kramp, K., Jastrzebska, B., Jin, H., Feng, Z.* and Palczewski, K.* (*: Contact authors) (2011) Heterologous expression of functional G protein-coupled receptors in Caenorhabditis elegans. FASEB J.[E-pub ahead of print] doi: 10.1096/fj.11-197780
Cao, P., Sun, W., Kramp, K., Zheng, M., Salom, D., Jastrzebska. B., Jin, H., Palczewski, K.* and Feng, Z.* (*: Contact authors) (2011) Light-sensitive coupling of the G protein-coupled receptors rhodopsin and melanopsin to Gi/o and Gq signal transduction in Caenorhabditis elegans. FASEB J.[E-pub ahead of print] doi: 10.1096/fj.11-197798
Zheng, M., Gorlenkova, O., Yang, J. and Feng, Z. (2011) A liquid phase based C. elegans behavioral analysis system identifies motor activity loss in a nematode Parkinson's disease model. J. Neurosci. Meth. doi:10.1016/j.jneumetho.2011.11.015.