Spinocerebellar ataxia type 3, also known as Machado-Joseph disease (SCA3/MJD), is a dominantly inherited neurological disorder characterized by progressive difficulties with coordination and brainstem function. SCA3/MJD is one of at least eight neurodegenerative diseases now known to be caused by an expanded CAG repeat that encodes a polyglutamine domain in the disease protein. Increasing evidence indicates that expanded polygln in itself the factor that is toxic to neurons in these diseases, and that this toxicity stems from polygln s tendency to misfold and aggregate. The overall goal of the proposed studies is to determine the mechanism of neuronal death in this group of diseases. Our hypothesis is that misfolding and aggregation of the disease protein within the nucleus of the neuron is the underlying toxic event in these diseases. The proposed experiments aim to answer how misfolding and aggregation of the SCA3/MJD disease protein compromises cellular function, ultimately leading to cell death. Studies will: 1) characterize the metabolic consequences of polyglutamine misfolding and aggregation; 2) address whether aggregates are a cause or consequence of the disease process; and 3) characterize genetic and cellular factors that modify polygln aggregation and toxicity. The proposed experiments should provide insight into the common mechanism underlying an important group of inherited human diseases, and may identify potential targets for therapeutic intervention in SCA3/MJD and related neurological disorders. Moreover, because protein misfolding is now recognized to be central to many of the most common forms of neurodegenerative disease (including Alzheimer and Parkinson disease), the proposed studies may prove to be relevant more broadly to such diseases as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038712-04
Application #
6625459
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Gwinn, Katrina
Project Start
2000-01-01
Project End
2004-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
4
Fiscal Year
2003
Total Cost
$267,726
Indirect Cost
Name
University of Iowa
Department
Neurology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Duda, Marlena; Zhang, Hongjiu; Li, Hong-Dong et al. (2018) Brain-specific functional relationship networks inform autism spectrum disorder gene prediction. Transl Psychiatry 8:56
McLoughlin, Hayley S; Moore, Lauren R; Chopra, Ravi et al. (2018) Oligonucleotide therapy mitigates disease in spinocerebellar ataxia type 3 mice. Ann Neurol 84:64-77
Sutton, Joanna R; Blount, Jessica R; Libohova, Kozeta et al. (2017) Interaction of the polyglutamine protein ataxin-3 with Rad23 regulates toxicity in Drosophila models of Spinocerebellar Ataxia Type 3. Hum Mol Genet 26:1419-1431
Ramani, Biswarathan; Panwar, Bharat; Moore, Lauren R et al. (2017) Comparison of spinocerebellar ataxia type 3 mouse models identifies early gain-of-function, cell-autonomous transcriptional changes in oligodendrocytes. Hum Mol Genet 26:3362-3374
Ramani, Biswarathan; Harris, Ginny M; Huang, Rogerio et al. (2017) A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript. Hum Mol Genet 26:3232-3233
Moore, Lauren R; Rajpal, Gautam; Dillingham, Ian T et al. (2017) Evaluation of Antisense Oligonucleotides Targeting ATXN3 in SCA3 Mouse Models. Mol Ther Nucleic Acids 7:200-210
Costa, Maria do Carmo; Ashraf, Naila S; Fischer, Svetlana et al. (2016) Unbiased screen identifies aripiprazole as a modulator of abundance of the polyglutamine disease protein, ataxin-3. Brain 139:2891-2908
Faggiano, Serena; Alfano, Caterina; Pastore, Annalisa (2016) The missing links to link ubiquitin: Methods for the enzymatic production of polyubiquitin chains. Anal Biochem 492:82-90
Ramani, Biswarathan; Harris, Ginny M; Huang, Rogerio et al. (2015) A knockin mouse model of spinocerebellar ataxia type 3 exhibits prominent aggregate pathology and aberrant splicing of the disease gene transcript. Hum Mol Genet 24:1211-24
Faggiano, Serena; Menon, Rajesh P; Kelly, Geoff P et al. (2015) Allosteric regulation of deubiquitylase activity through ubiquitination. Front Mol Biosci 2:2

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