The ultimate goal of this project is to gain insight into polyglutamine-induced neurodegeneration by identifying genes, pathways and molecular mechanisms involved in the pathogenesis of spinocerebellar ataxia type 1 (SCA1). A Drosophila model of SCA1 was created by generating flies that express either normal or expanded human SCA1 transgenes. This fly model recapitulates the cellular phenotypes observed in SCA1 patients including the formation of nuclear inclusions (NI) and progressive neuronal degeneration. Capitalizing on the power of Drosophila genetics, two large genetic screens were designed to identify genes that modify a SCA1 neurodegenerative phenotype in the eye. The first screen yielded modifiers of the SCA1 phenotype when gene activity was decreased; the second screen yielded SCA1 modifiers when gene activity was increased. Both suppressors and enhancers of the neurodegenerative phenotype were obtained from each screen.
The first aim of the proposed work is to identify the genes that modify the SCA1 neurodegenerative phenotype. These modifiers will be further characterized in sensitive viability and locomoter assays that allow the quantification of their modifier effects. The most powerful suppressors will be selected for further studies. To investigate whether different polyglutamine disease share common mechanisms of pathogenesis, the SCA1 modifiers will be tested in fly models of Huntington disease and polyglutamine toxicity. Finally, because the normal function of the SCA1 gene may be relevant to pathogenesis, the function of the Drosophila SCA1 gene will be investigated by generating lack-of-function mutations and transgenes for its over expression. In future studies, the most promising SCA1 suppressors characterized in flies will be investigated in the SCA1 mouse model, and in mouse models of polyglutamine disease. These genes may also be relevant to research aimed at treating other neurodegenerative proteinopathies such as Alzheimer disease and Parkinson disease. They will provide valuable targets for future pharmacological research aimed at developing drugs for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS042179-01S1
Application #
6484917
Study Section
Special Emphasis Panel (ZRG1 (02))
Program Officer
Oliver, Eugene J
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$50,000
Indirect Cost
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Al-Ramahi, Ismael; Lu, Boxun; Di Paola, Simone et al. (2018) High-Throughput Functional Analysis Distinguishes Pathogenic, Nonpathogenic, and Compensatory Transcriptional Changes in Neurodegeneration. Cell Syst 7:28-40.e4
Bouché, Valentina; Espinosa, Alma Perez; Leone, Luigi et al. (2016) Drosophila Mitf regulates the V-ATPase and the lysosomal-autophagic pathway. Autophagy 12:484-98
Yao, Yuwei; Cui, Xiaotian; Al-Ramahi, Ismael et al. (2015) A striatal-enriched intronic GPCR modulates huntingtin levels and toxicity. Elife 4:
Calap-Quintana, Pablo; Soriano, Sirena; Llorens, José Vicente et al. (2015) TORC1 Inhibition by Rapamycin Promotes Antioxidant Defences in a Drosophila Model of Friedreich's Ataxia. PLoS One 10:e0132376
Lu, Xiao-Hong; Mattis, Virginia B; Wang, Nan et al. (2014) Targeting ATM ameliorates mutant Huntingtin toxicity in cell and animal models of Huntington's disease. Sci Transl Med 6:268ra178
de Haro, Maria; Al-Ramahi, Ismael; Jones, Karlie R et al. (2013) Smaug/SAMD4A restores translational activity of CUGBP1 and suppresses CUG-induced myopathy. PLoS Genet 9:e1003445
Holth, Jerrah K; Bomben, Valerie C; Reed, J Graham et al. (2013) Tau loss attenuates neuronal network hyperexcitability in mouse and Drosophila genetic models of epilepsy. J Neurosci 33:1651-9
Park, Jeehye; Al-Ramahi, Ismael; Tan, Qiumin et al. (2013) RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498:325-331
Miller, John P; Yates, Bridget E; Al-Ramahi, Ismael et al. (2012) A genome-scale RNA-interference screen identifies RRAS signaling as a pathologic feature of Huntington's disease. PLoS Genet 8:e1003042
Zhang, Ningzhe; Li, Bensheng; Al-Ramahi, Ismael et al. (2012) Inhibition of lipid signaling enzyme diacylglycerol kinase epsilon attenuates mutant huntingtin toxicity. J Biol Chem 287:21204-13

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