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Laboratories
Molecular Neurobiology
The laboratory of Molecular Neurobiology focuses on the application of molecular biologic techniques to study neurodegenerative diseases and other neuropsychiatric conditions. We have a particular interest in the pathogenesis of polyglutamine neurodegenerative disorders such as Huntington's disease and Dentatorubral pallidoluysian atrophy (DRPLA). We have conducted biochemical and cell biological studies of the HD gene product, termed "huntingtin." We have developed a number of cell culture models of HD and DRPLA, and several different transgenic mouse models. These models are being studied to gain an understanding of the pathogenesis of the disorder, and also to assist in the development of novel therapeutic agents. We have applied similar techniques for the study of Parkinsons' disease (PD). We have identified a novel protein involved in the pathogenesis of PD, and we have developed cellular models of the disease. We are also applying similar techniques to psychiatric conditions such as Bipolar Affective disorder and Schizophrenia. The laboratory offers the opportunity to study of these diseases to undergraduates, graduate students, postdoctoral fellows and other interested scientists. Previous trainees of the laboratory have been very successful in developing independent research careers and faculty appointments both in the United States and abroad. Laboratory Faculty Laboratory Staff Recent Findings and Current Research Some of our current studies focus on the molecular pathway by which aggregates of huntingtin protein are generated in cells. We hypothesized that intermediates in this aggregation pathway, may be important for HD pathogenesis, thus excellent targets for future therapeutics. In addition, the laboratory has generated an inducible transgenic mouse model of HD. Expression of the mutant huntingtin protein can be turned on and off using a chemical trigger. This model is likely to be very useful for understanding the sequence of events that leads to HD toxicity, and also is likely to be very useful for therapeutic studies.
We have also studied the pathogenesis of Parkinson's disease. One of the causes of familial Parkinson's disease involves mutations in the alpha synuclein protein. The laboratory identified the first protein interactor for alpha synuclein, which was termed synphilin-1 and collaborated with other groups to show synphilin-1 is present in Lewy bodies the pathologic hallmark of PD. The laboratory has also cell model of Parkinson's disease, which is likely to be useful for pathologic studies. We have recently collaborated with Ted Dawson's lab to identify synphilin-1 as a molecular target of parkin a protein also involved in genetic PD.
We have also studied the disease closely related to HD termed Dentatorubral pallidoluysian atrophy (DRPLA). The laboratory generated the first mouse model of DRPLA and is currently involved in studying the pathogenesis of this disease. We have also studied genetics of psychiatric disorders including affective disorders and schizophrenia, and are beginning candidate gene and mouse model studies of schizophrenia. Recent Publications
Y. Ozeki, T. Tomoda, J. Kleiderlein, A. Kamiya, L. Bord, K. Fujii, M.
Okawa, N. Yamada, M. E Hatten, S.H. Snyder, C. A. Ross, A. Sawa
Engelender S, Kaminsky Z, Guo X, Sharp AH, Amaravi RK, Kleiderlein JJ,
Margolis RL, Troncoso JC, Lanahan AA, Worley PF, Dawson VL, Dawson TM,
Ross, CA. Synphilin-1 associates with a-synuclein and promotes the formation
of cytosolic inclusions. Nature Genetics 22:110-114, 1999.
Schilling G., Coonfield ML., Ross CA., Borchelt DR. Coenzyme Q10 and Remacemide hydrochloride Ameliorate Motor Deficits in a Transgenic HD Mouse Model. Neuroscience Letters 315:149-53 (2001). Tanaka, Y, Engelender S, Igarashi S, Rao, R, Wanner T., Tanzi R, Sawa A, Dawson VL, Dawson, TM, Ross CA. Inducible expression of mutant a-synuclein decreases proteasome activity and increases sensitivity to mitochondria-dependent apoptosis. Human Molecular Genetics 10 9:919-26, 2001. |
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