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Molecular Neurobiology Laboratory

Faculty Director: Christopher A. Ross M.D., Ph.D.

Link to PubMed publications for Ross CA
            
The molecular neurobiology lab focuses on the application of 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 (HD). We use cell and transgenic mouse models to gain an understanding of the pathogenesis of the disorder, and also to assist in the development of novel therapeutic techniques. We have applied similar techniques for the study of Parkinson’s disease (PD). We have identified several novel proteins involved in the pathogenesis of PD, and we have cell and mouse models of the disease. We are also applying similar techniques to psychiatric conditions such as bipolar disorder and schizophrenia.

The laboratory offers research opportunities 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 in the United States and abroad.

LAB MEMBERS

Omidreza Firuzi, M.D., Ph.D. - Postdoctoral Fellow
Haibing Jiang, Ph.D. - Postdoctoral Fellow
Yideng Liang, M.D., Ph.D. - Postdoctoral Fellow
Naoki Masuda, Md., Ph.D. - Postdoctoral Fellow
Fred Nucifora, D.O., Ph.D. -Postdoctoral Fellow
Ricky Hischhorn, Ph.D. - Visiting Scientist
Tamara Ratovitski, M.S. - Research Associate
Xiaofang Wang - Mouse Lab Technician
Erin Watkin - Graduate Student
Eileen Kasda - Administrative Manager

RECENT FINDINGS AND CURRENT RESEARCH

Huntington’s Disease

Our laboratory has conducted a wide range of studies since the discovery of the HD gene mutation in 1993. The laboratory mapped the expression pattern of the HD gene and its protein product, huntingtin. We identified the first protein interacting with huntingtin, HAP1. Studies conducted in the laboratory generated some of the first cellular models of HD, and identified the cell nucleus as an important site of HD toxicity. In addition, in collaboration with David Borchelt's lab, we generated one of the initial mouse models of HD, which has subsequently been used in many studies of HD pathogenesis and HD therapeutics. Our HD studies take advantage of the presence of the Baltimore Huntington's Disease Center, directed by Dr. Ross, and providing opportunities for clinical correlations. 

Nucifora_CBP 
CELLULAR TOXICITY OF MUTANT HUNTINGIN: Left panel: primary neuron transfected with wild type huntingtin (Htt) is healthy.  Middle panel: neuron transfected with mutant Htt is atrophic and dying.  Right panel: neuron transfected with mutant Htt plus CBP transcriptional activator shows rescue of toxicity.  

Our current studies focus aspects of pathogenesis which may be good targets for therapeutic intervention. We study posttranslational modification, including proteolytic cleavage of huntingtin, which is believed to be a critical step in pathogenesis, since enzymes such as kinases and proteases may be targeted by small molecules that can be used as drugs.  We also study gene transcription, since drugs such as HDAC inhibitors are available to modify it. In collaboration with Michelle Poirier’s lab, we study the molecular pathway by which aggregates of huntingtin protein are generated in cells, since this aggregation pathway may be a target for future therapeutics. In collaboration with Wenzhen Duan’s lab, we conduct preclinical therapeutic trials of candidate therapeutic agents. We also focus on the generation of novel cell and mouse models. 

Mouse Model

TRANSGENIC MOUSE MODEL OF HUNTINGTON’S DISEASE: 

Panel A: normal mouse; B: transgenic mouse expressing an N-terminal fragment of mutant Htt has lost weight and is hypoactive; C: normal mouse attempts to escape when suspended by the tail; D: transgenic mouse assumes an abnormal rigid and dystonic posture when suspended by the tail.  This model is now used for studying pathogenesis and testing experimental therapeutics for HD.

Parkinson’s disease

Parkinson's disease (PD), like HD, involves selective neuronal degeneration, but unlike HD, several genes can cause PD, suggesting the possibility of a pathogenic pathway. Many of our PD studies are conducted as part of the Morris K. Udall Parkinson's Disease Center Center, directed by Ted Dawson. One of the causes of familial PD involves mutations in the alpha synuclein protein. The laboratory identified the first protein interactor for alpha-synuclein, which we 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 developed alpha-synuclein cell models of PD, likely to be useful for pathologic studies. We are currently studying the aggregation pathway of alpha-synuclein, in collaboration with Michelle Poirier’s lab, and using the cell models we have developed for testing therapeutic agents, in collaboration with Wenzhen Duan’s lab

Familial PD can also be caused by mutations in LRRK2, and one of the mutations (G2019S) is the most common currently known cause of typical late onset PD. We have studied LRRK2 in collaboration with Wanli Smith’s lab. We have developed cell models, and shown that cell toxicity of mutant LRRK2 is dependent on its kinase activity. This makes LRRK2 a very promising therapeutic target. We are currently searching for protein interacting partners of LRRK2, developing further cell models, and developing transgenic mouse models in order to test the role of kinase activity and protein interactions, and in order to begin preclinical therapeutic studies. 

Schizophrenia

Similar techniques are now being used to study schizophrenia. Unlike the degenerative diseases, schizophrenia is believed to be caused by abnormal neurodevelopment. The candidate gene Disrupted in Schizophrenia-1 (DISC-1) is mutated in a familial form of schizophrenia. DISC-1 interacts with a number of proteins implicated in neuronal development and mutations of DISC1 interfere with neuronal differentiation and development both in vitro and in vivo. We have developed cell and mouse models using mutant DISC-1. These are primarily being done in the lab of Mikhail Pletnikov (see his description for more details). These may shed light on the neurodevelopmental origin of schizophrenia. Additional studies are needed to identify additional interaction partners of DISC-1, and identify interactions between DISC-1 and other schizophrenia genes and environmental risk factors.   

See also the Department's Schizophrenia Program

SELECTED PUBLICATIONS

Ross CA, Margolis RL, Reading SA, Pletnikov M, Coyle JT. Neurobiology of schizophrenia. Neuron. 2006 Oct 5;52(1):139-53.

Pletnikov MV, Ayhan Y, Xu Y, Nikolskaia O, Ovanesov M, Huang H, Mori, S, Moran TH, Ross CA Inducible expression of mutant human DISC1 in mice is associated with brain and behavioral abnormalities reminiscent of schizophrenia. Mol. Psychiatry 2007.
 
Smith WW, Pei Z, Jiang H, Dawson VL, Dawson TM, Ross CA. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nature Neurosci. 2006 Oct;9(10):1231-3.

Pletnikov MV, Xu Y, Ovanesov MV, Kamiya A, Sawa A, Ross CA.  PC12 cell model of inducible expression of mutant DISC1: New evidence for a dominant-negative mechanism of abnormal neuronal differentiation. Neurosci Res. 2007 Jul;58(3):234-44.

Smith WW, Pei Z, Jiang H, Moore DJ, Liang Y, West AB, Dawson VL, Dawson TM, Ross CA. Leucine-rich repeat kinase 2 (LRRK2) interacts with parkin, and mutant LRRK2 induces neuronal degeneration. Proc Natl Acad Sci U S A. 2005 Dec 20;102(51):18676-81.

Ross CA, Poirier MA. What is the role of protein aggregation in neurodegeneration? Nat Rev Mol Cell Biol. 2005 Nov;6(11):891-8.

Wang W, Duan W, Igarashi S, Morita H, Nakamura M, Ross CA. Compounds blocking mutant huntingtin toxicity identified using a Huntington's disease neuronal cell model. Neurobiol Dis. 2005 Nov;20(2):500-8.

Ross CA, Poirier MA. Protein aggregation and neurodegenerative disease. Nature Medicine 2004 Jul;10 Suppl:S10-7.

Ross CA. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron.2002 Aug 29;35(5):819-22.

Nucifora FC Jr, Sasaki M, Peters MF, Huang H, Cooper JK, Yamada M, Takahashi H, Tsuji S, Troncoso J, Dawson VL, Dawson TM, Ross CA. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science. 2001 Mar 23;291(5512):2423-8.

 
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