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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS056224-05
Application #
8204671
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Gwinn, Katrina
Project Start
2007-12-15
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2013-11-30
Support Year
5
Fiscal Year
2012
Total Cost
$336,569
Indirect Cost
$122,194
Name
University of Texas Sw Medical Center Dallas
Department
Physiology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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
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
Liang, Xia; Wu, Jun; Egorova, Polina et al. (2014) An automated and quantitative method to evaluate progression of striatal pathology in Huntington's disease transgenic mice. J Huntingtons Dis 3:343-50
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
Kim, Meewhi (2014) Pathogenic polyglutamine expansion length correlates with polarity of the flanking sequences. Mol Neurodegener 9:45
Bezprozvanny, Ilya (2013) Bilayer measurement of endoplasmic reticulum Ca2+ channels. Cold Spring Harb Protoc 2013:
Bezprozvanny, Ilya (2013) Reconstitution of endoplasmic reticulum InsP3 receptors into black lipid membranes. Cold Spring Harb Protoc 2013:
Bezprozvanny, Ilya; Hiesinger, Peter Robin (2013) The synaptic maintenance problem: membrane recycling, Ca2+ homeostasis and late onset degeneration. Mol Neurodegener 8:23

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