The long-term goal of our laboratory is to understand the cellular basis of neurodegeneration. We are testing the idea that neurodegeneration results from derangements in relatively few but strategic sub-cellular pathways. By identifying critical components of these pathways one could begin to not only understand the biology of neurodegeneration, but also embark on the design of novel therapeutic agents.
We are currently studying the autosomal dominant disorder Spinocerebellar Ataxia Type 1 (SCA1), a relentless disease that affects cerebellar Purkinje cells and brainstem neurons. This disorder is caused by a polyglutamine expansion in the involved disease protein and is thus similar to a growing number of disorders, including Huntington disease, that share this mutational mechanism. Patients with SCA1 begin to display cerebellar signs characterized by motor incoordination or ataxia in early to mid adulthood. Unfortunately there is no treatment for this disease and patients eventually succumb from the complications of brainstem dysfunction.
The protein involved in SCA1, called ataxin-1, interacts with a multifaceted protein called LANP in a glutamine-length dependent manner. Several cellular functions have been ascribed to LANP including the regulation of key cellular processes such as cytoskeletal dynamics, vesicular transport, RNA transport, transcription, apoptosis and intracellular signaling. Moreover LANP is expressed in abundance in Purkinje cells the site of SCA1 pathogenesis. We are testing the hypothesis that some aspects of SCA1 might be explained by an exaggerated affinity of the expanded version of ataxin-1 for LANP; either LANP binds to expanded ataxin-1 and is prevented from pursuing its normal function, or the ataxin-1/LANP complex is a toxic partnership that brings about neuronal degeneration. To understand LANP’s functions in neurons, we are using a variety of biochemical, cell and molecular biological techniques. We have also generated an LANP knock-out mouse that will help us elucidate LANP’s functions and clarify its role in polyglutamine induced degeneration.
We have recently expanded our interests to encompass other genetic neurological disorders that appear to have defects in proteins involved in vesicular transport and cytoskeletal dynamics; and at a cellular level display features in common with polyglutamine induced degeneration.
Publications:
Opal, P., Garcia, J.J., McCall, A., Xu, B., Weeber, E.J., Sweatt, J.D., Orr, H.T., and Zoghbi, H.Y. Generation and characterization of LANP/pp32 null mice. Molecular and Cellular Biology 8, 3140-9 (2004).
Opal, P., Garcia, J.J., Propst, F., Matilla, A., Orr, H.T. and Zoghbi, H. Mapmodulin/LANP binds the light chain of microtubule associated protein 1B and modulates neuritogenesis. Journal of Biological Chemistry, 278, 34691-9 (2003).
Opal, P. and Zoghbi, H.Y. The role of chaperones in polyglutamine disease. Trends in Molecular Medicine 8: 232-236 (2002).
Opal, P, Tintner, R., Jankovic, J., Leung, J., Breakefield, X.O., Friedman, J and Ozelius, L. Intrafamilial phenotypic variability of the DYT1 dystonia. From asymptomatic TOR1A gene carrier status to dystonic storm. Movement Disorders 17, 339-342 (2002).
Cummings, C.J, Sun, Y., Opal, P., Antalffy, B, Mestril, R., Orr, H.T., Dillman, W.H. and Zoghbi, H.Y. Overexpression of inducible HSP70 chaperone suppresses neuropathology and involves motor function in SCA1 mice. Human Molecular Genetics 10: 1511-1518 (2001).
