Expansion of a polyglutamine (polyQ) tract is the basis of several inherited neurodegenerative diseases including spinocerebellar ataxia type 2 (SCA2). Polyglutamine diseases share several features, most importantly, the presence of intranuclear neuronal aggregates in disease brains. However, pathogenesis leading to neurodegeneration in SCA2 may differ in that the pathologic polyQ tracts in ataxin-2, the SCA2 gene product, are relatively short and intranuclear aggregates have not been found. Four hypotheses will be tested: 1) the ER exist motif, clathrin mediated sorting signal and self-association domain in ataxin-2 are functional and are important for pathogenesis. 2) Expression of full- length ataxin-2 in mouse Purkinje cells in vivo causes dysfunction and neurodegeneration. 3) The interaction of ataxin-2 with a novel binding protein, A2BP1, is important for pathogenesis. 4) Proteolytic cleavage of ataxin-2 increases pathogenesis. To evaluate these hypotheses two specific aims are proposed: In the first aim, cultured cells and human tissues will be used to determine the subcellular localization and proteolytic processing of normal and mutated ataxin-2. The consequences of deleting specific domains will be analyzed. The interaction of A2BP1with ataxin-2 will be characterized, especially as it relates to the self-interaction of ataxin-2. Studies in the second aim will determine which domains in ataxin-2 are necessary for pathogenesis in vivo. Based on the results in aim 1, transgenic mice expressing ataxin-2 with normal and pathologic polyQ tracts will be generated, as well as mice expressing ataxin-2 with deletions or point mutations in specific domains. Mice will be compared on tests of motor ability. The deletion of point mutations in specific domains. Mice will be compared on tests of motor ability. The extent of changes in cerebellar Purkinje cells will be examined with anatomical techniques. The ultimate goal of this proposal is to define the necessary molecular components of SCA2 pathogenesis and to contribute to the understanding of neurodegenerative diseases in general.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS033123-05
Application #
6051066
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Spinella, Giovanna M
Project Start
1996-02-01
Project End
2004-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
5
Fiscal Year
2000
Total Cost
$272,943
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Figueroa, Karla P; Gan, Shi-Rui; Perlman, Susan et al. (2018) C9orf72 repeat expansions as genetic modifiers for depression in spinocerebellar ataxias. Mov Disord 33:497-498
Scoles, Daniel R; Pulst, Stefan M (2018) Spinocerebellar Ataxia Type 2. Adv Exp Med Biol 1049:175-195
Scoles, Daniel R; Meera, Pratap; Schneider, Matthew D et al. (2017) Antisense oligonucleotide therapy for spinocerebellar ataxia type 2. Nature 544:362-366
Meera, Pratap; Pulst, Stefan; Otis, Thomas (2017) A positive feedback loop linking enhanced mGluR function and basal calcium in spinocerebellar ataxia type 2. Elife 6:
Pflieger, Lance T; Dansithong, Warunee; Paul, Sharan et al. (2017) Gene co-expression network analysis for identifying modules and functionally enriched pathways in SCA2. Hum Mol Genet 26:3069-3080
Graf, Julia; Hellenbroich, Yorck; Veelken, Norbert et al. (2016) Two different genetic diseases in the same patient: Coincident, concomitant, or causally related? Mov Disord 31:491-2
Scoles, Daniel R; Ho, Mi H T; Dansithong, Warunee et al. (2015) Repeat Associated Non-AUG Translation (RAN Translation) Dependent on Sequence Downstream of the ATXN2 CAG Repeat. PLoS One 10:e0128769
Dansithong, Warunee; Paul, Sharan; Figueroa, Karla P et al. (2015) Ataxin-2 regulates RGS8 translation in a new BAC-SCA2 transgenic mouse model. PLoS Genet 11:e1005182
Matilla-DueƱas, A; Ashizawa, T; Brice, A et al. (2014) Consensus paper: pathological mechanisms underlying neurodegeneration in spinocerebellar ataxias. Cerebellum 13:269-302
Neuenschwander, Annalese G; Thai, Khanh K; Figueroa, Karla P et al. (2014) Amyotrophic lateral sclerosis risk for spinocerebellar ataxia type 2 ATXN2 CAG repeat alleles: a meta-analysis. JAMA Neurol 71:1529-34

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