The broad, long-term objective of the project is to understand the molecular basis for neurodegeneration in polyglutamine (polyQ) expansion disorders. The polyQ-expansion disorders belong to the family of autosomal-dominant and lethal neurodegenerative diseases that share a common molecular trigger (CAG repeat expansion). A number of toxic functions have been assigned to the polyQ-expanded proteins, but so far clear understanding of pathogenic mechanisms involved in these disorders is lacking. None of the polyQ- expansion disorders have a cure. Huntington's disease (HD) is the most extensively studied among polyQ- expansion disorders. Striatal medium spiny neurons (MSN) are selectively affected in HD. PolyQ-expansion in Huntingtin protein (Httexp) is a molecular cause of HD. My laboratory recently discovered that Httexp directly binds to and activates the type 1 inositol 1,4,5-trisphosphate receptor (InsP3R1), an intracellular Ca2+ release channel. Furthermore, we demonstrated a direct connection between abnormal neuronal Ca2+ signaling and apoptosis of HD MSN in in vitro experiments. Now I propose to further test """"""""Ca2+ hypothesis of HD"""""""". I also propose to apply similar ideas to understanding the mechanisms of pathogenesis in spinocerebellar ataxia type 3 (SCA3), another member of polyQ-expansion disorders family. Specifically, I propose: 1. To analyze biochemical and functional interactions between InsP3R1 and polyQ-expanded Huntingtin protein. To test """"""""Ca2+ hypothesis of HD"""""""" in experiments with HD-YAC128 mouse model of HD. 2. To analyze biochemical and functional interactions between InsP3R1 and polyQ-expanded ataxin-3 protein. To test """"""""Ca2+ hypothesis of SCA3"""""""" in experiments with SCA3-YAC84Q mouse model of SCA3. 3. To validate our results in Ca2+ imaging and biochemical experiments with primary fibroblasts from human HD and SCA3 patients Our experiments will provide a critical test for a role of deranged Ca2+ signaling in pathogenesis of HD and SCA3 and may have implications for understanding and treatment of other polyQ-expansion disorders. The proposed project will have direct and immediate relevance for public health. Huntington's disease (HD) and Spinocerebellar Ataxia type 3 (SCA3) are incurable genetic disorders that cause enormous suffering. The experiments described in the grant are aimed at testing specific hypothesis regarding pathogenesis of these diseases and will provide information critical for development of the cure.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gwinn, Katrina
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Wu, Jun; Ryskamp, Daniel; Birnbaumer, Lutz et al. (2018) Inhibition of TRPC1-Dependent Store-Operated Calcium Entry Improves Synaptic Stability and Motor Performance in a Mouse Model of Huntington's Disease. J Huntingtons Dis 7:35-50
Egorova, Polina A; Gavrilova, Alexandra V; Bezprozvanny, Ilya B (2018) In Vivo Analysis of the Climbing Fiber-Purkinje Cell Circuit in SCA2-58Q Transgenic Mouse Model. Cerebellum :
Pchitskaya, Ekaterina; Popugaeva, Elena; Bezprozvanny, Ilya (2018) Calcium signaling and molecular mechanisms underlying neurodegenerative diseases. Cell Calcium 70:87-94
Ryskamp, Daniel; Wu, Jun; Geva, Michal et al. (2017) The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease. Neurobiol Dis 97:46-59
Zhemkov, Vladimir A; Kulminskaya, Anna A; Bezprozvanny, Ilya B et al. (2016) The 2.2-Angstrom resolution crystal structure of the carboxy-terminal region of ataxin-3. FEBS Open Bio 6:168-78
Wu, Jun; Ryskamp, Daniel A; Liang, Xia et al. (2016) Enhanced Store-Operated Calcium Entry Leads to Striatal Synaptic Loss in a Huntington's Disease Mouse Model. J Neurosci 36:125-41
Egorova, Polina A; Zakharova, Olga A; Vlasova, Olga L et al. (2016) In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model. J Neurophysiol 115:2840-51
Zhang, Zilai; Cao, Mou; Chang, Chia-Wei et al. (2016) Autism-Associated Chromatin Regulator Brg1/SmarcA4 Is Required for Synapse Development and Myocyte Enhancer Factor 2-Mediated Synapse Remodeling. Mol Cell Biol 36:70-83
Egorova, Polina; Popugaeva, Elena; Bezprozvanny, Ilya (2015) Disturbed calcium signaling in spinocerebellar ataxias and Alzheimer's disease. Semin Cell Dev Biol 40:127-33
Fedorenko, Olena A; Popugaeva, Elena; Enomoto, Masahiro et al. (2014) Intracellular calcium channels: inositol-1,4,5-trisphosphate receptors. Eur J Pharmacol 739:39-48

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