Faculty Director: Wanli W. Smith, M.D., Ph.D.
The cellular neurobiology laboratory is interested in unraveling the cellular signaling pathways in pathogenesis of neurodegenerative diseases and other disorders such as obesity. There are four areas of investigation including: (1) the study of the mechanisms of neuronal cell death; (2) the study of protein aggregation and clearance pathways; (3) the study of the molecular basis of Parkinson's disease (PD), Alzheimer’s disease (AD) and obesity; and (4) testing innovative neuroprotective compounds using cell, fly, and mouse models. We have elucidated the role of alpha-synuclein in cell toxicity and protein aggregation, interaction with stress and the underlying cellular pathways in PD, and demonstrated that activation of the p66Shc/JNK/forkhead pathway mediates amyloid beta peptide-induced cell death in AD. Mutations in LRRK2 have recently been found to cause autosomal dominant PD with multiple pathology and some cases of sporadic PD. We have demonstrated that LRRK2 induces neuronal death and interacts with parkin. We further found that LRRK2 has kinase activity, which is regulated by GTP via the intrinsic GTPase Roc domain, and that alterations of the LRRK2 protein that reduce kinase activity of mutant LRRK2 correspondingly reduces neuronal toxicity. Our studies aim to illuminate the disease pathogenesis and to suggest novel therapeutic targets for intervention.
Fellows, graduate, and undergraduate students, who are interested in this research and would like to join the lab are encouraged to contact Dr. Smith directly.
Zhaohui Liu, Ph.D. postdoctoral fellow
Xueping Li, Ph.D. student
Yi Yu, MS, technician
Wanli W. Smith, Zhong Pei, Haibing Jiang, Valina L. Dawson, Ted M. Dawson, Christopher A. Ross. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nature Neuroscience, 2006, 9(10):1231-3
Wanli. W. Smith, R.L. Margolis, X. Li, J.C. Troncoso, M.K. Lee, V.L.Dawson, T.M. Dawson, T. Iwatsubo, and C.A. Ross. Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in Sh-Sy5Y cells. J. Neurosci. 2005 8;25(23):5544-52
Wanli W. Smith, Darrell D. Norton, Myriam Gorospe, Haibing Jiang, Nikki J. Holbrook, Shino Nemoto, Toren Finkel, John W. Kusiak. Phosphorylation of p66Shc and forkhead proteins mediates Ab toxicity. J Cell Biol. 2005, 25;169(2):331-9.
Wanli W. Smith, Haibing Jiang, Zhong Pei, Yuji Tanaka, Hokuto Morita, Akira Sawa, Valina L. Dawson, Ted M. Dawson and Christopher A. Ross. Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha synuclein-induced toxicity. Endoplasmic reticulum stress and mitochondrial cell death pathways mediate A53T mutant alpha-synuclein-induced toxicity. Hum Mol Genet. 2005, 14(24):3801-11.
Wanli W. Smith, Zhong Pei, Haibing Jiang, Darren J. Moore, Yideng Liang, Andrew B. West, Valina L. Dawson, Ted M. Dawson, and Christopher A. Ross. LRRK2: Interaction with parkin and mutation-induced neuronal degeneration. Proc Natl Acad Sci U S A. 2005, 102(51):18676-81.