Spinocerebellar ataxia-1 (SCA-1) belongs to a group of dominantly inherited neurodegenerative diseases caused by a mutant expansion of a polyglutamine-repeated sequence within the affected gene product ataxin-1. One of the major cell types affected by ataxin-1 is the cerebellar Purkinje cell. The mechanism by which ataxin-1 causes Purkinje cell degeneration in SCA-1 is not known, however, ataxin-1 down regulates Purkinje cell specific proteins involved in calcium homeostasis and signaling in patients with SCA-1, and in presymptomatic SCA-1 transgenic mice. Therefore, the present proposal is designed to determine if targeted deprivation of one of the specific proteins involved in calcium homeostasis will further enhance ataxin-1 toxicity and if trophic upregulation of this protein will rescue SCA-1 Purkinje cells from degeneration. The long-term goal of this project is to understand the role of calcium signaling pathways in neuronal degeneration in order to design therapeutic approaches in clinical management of SCA-1 and other dominantly inherited cerebellar ataxias. To determine if decreased expression of calcium binding protein calbindin-D 28k (CAB) will increase the toxic effects of ataxin-1 on Purkinje cells, double mutant mice will be generated by mating CaB null mice with SCA-1 transgenic mice. To determine if overexpression of insulin-like growth factor - I (IGF-I) will rescue SCA-1 Purkinje cells from degeneration, double mutant mice will be generated by mating mice overexpressing IGF-I with SCA-1 transgenic mice. The changes in Purkinje cells will be assessed by behavioral, biochemical, immunochemical and immunohistochemical methods, focusing on the alterations in the expression of Purkinje cell markers, calcium binding proteins, and proteins involved in calcium signaling. Purkinje cells cultured from 0-1 day old SCA-1 transgenic mice will be used to determine if cultured Purkinje cells expressing mutant ataxin-1 show (i) altered expression of calcium binding proteins and proteins involved in calcium signaling (ii) sensitivity to increased Ca 2+-influx (iii) altered response to the inhibitors of calcium-dependent proteases and (iv) if treatment with IGF-I can reverse ataxin-1 mediated pathological changes. Purkinje cell cultures from non-transgenic mice will be used as controls. Complementary analysis to compare changes in cultured Purkinje cells with those cultured from CaB null and transgenics with Huntington's disease will also be performed. Further, changes observed in SCA-1 patients and in transgenic mice will be compared with that in Machado-Joseph disease/SCA-3, other cerebellar ataxias and normal controls.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS041546-04
Application #
7008115
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Tagle, Danilo A
Project Start
2003-02-01
Project End
2009-07-31
Budget Start
2006-02-01
Budget End
2009-07-31
Support Year
4
Fiscal Year
2006
Total Cost
$171,619
Indirect Cost
Name
University of Mississippi Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
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Hearst, Scoty M; Lopez, Mariper E; Shao, Qingmei et al. (2010) Dopamine D2 receptor signaling modulates mutant ataxin-1 S776 phosphorylation and aggregation. J Neurochem 114:706-16
Vig, Parminder J S; Shao, Qingmei; Lopez, Maripar E (2009) Glial response to polyglutamine-mediated stress. Biosci Hypotheses 2:148-150
Vig, Parminder J S; Shao, Qingmei; Subramony, S H et al. (2009) Bergmann glial S100B activates myo-inositol monophosphatase 1 and Co-localizes to purkinje cell vacuoles in SCA1 transgenic mice. Cerebellum 8:231-44
Vig, P J S; Wei, J; Shao, Q et al. (2007) Role of tissue transglutaminase type 2 in calbindin-D28k interaction with ataxin-1. Neurosci Lett 420:53-7
Vig, P J S; Subramony, S H; D'Souza, D R et al. (2006) Intranasal administration of IGF-I improves behavior and Purkinje cell pathology in SCA1 mice. Brain Res Bull 69:573-9
Vig, Parminder J S; Lopez, Maripar E; Wei, Jinrong et al. (2006) Glial S100B Positive Vacuoles In Purkinje Cells: Earliest Morphological Abnormality In SCA1 Transgenic Mice. J Neurol Sci Turish 23:166-174
D'Souza, D R; Wei, J; Shao, Q et al. (2006) Tissue transglutaminase crosslinks ataxin-1: possible role in SCA1 pathogenesis. Neurosci Lett 409:5-9