The ultimate goal of this project is to identify molecular mechanisms of pathogenesis and potential therapeutic targets that are common to Spinocerebellar ataxias (SCAs). These are a group ~30 genetically heterogeneous neurodegenerative disorders that share neuropathological and clinical features such as atrophy of the cerebellum and loss of motor coordination and balance. Recent data points to unsuspected links among inherited ataxias. First, a protein- protein-interaction network for inherited ataxias revealed that many ataxia-causing proteins share interacting partners. Second, dAtaxin-2 (an orthologue of the protein responsible for SCA2) is a major modifier of Ataxin-1[82Q]-induced neurotoxicity in a Drosophila model of SCA1. Together, these observations suggest that SCAs, and perhaps other inherited ataxias may share molecular mechanisms of pathogenesis in addition to similar neuropathology and clinical features. This hypothesis predicts that SCAs have common genetic modifiers and potential therapeutic targets that remain unknown. Testing this hypothesis requires a thorough comparison of genetic modifiers and mechanisms of pathogenesis among different inherited ataxias. A genetic approach will be employed to identify modifiers of neurotoxicity caused by expanded Ataxin-1, Ataxin-2 and Ataxin-7, the proteins responsible for SCA1, SCA2 an SCA7. The work proposed here will address the following specific aims: 1) To investigate the molecular mechanisms by which partial loss of dAtaxin-2 function suppresses Ataxin-1[82Q]-induced neurodegeneration. 2) To screen the ataxia interactome for genetic modifiers of Ataxin-1[82Q]-induced neurotoxicity. 3) To test the Ataxin-1[82Q] genetic modifiers and the ataxia interactome in Drosophila models of SCA2 and SCA7. 4) To validate the genetic interaction between Ataxin-2 and Ataxin-1 in a knock-in mouse SCA1 model. Since these extensive comparative studies are impractical with mammalian models, we will use Drosophila models for the majority of the analysis and mouse models for validation of key interactions. The suppressors of neurodegeneration identified as a result of this work may directly point to specific therapeutic targets. These basic studies are prerequisite to developing therapies for these neurodegenerative disorders for which there are no effective treatments.

Public Health Relevance

The work in this proposal is aimed towards revealing mechanisms of pathogenesis and identifying potential therapeutic targets in Spinocerebellar ataxias. These basic studies are a prerequisite to developing therapies for these neurodegenerative disorders for which there are no effective treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS042179-09
Application #
8289572
Study Section
Cell Death in Neurodegeneration Study Section (CDIN)
Program Officer
Sutherland, Margaret L
Project Start
2001-07-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
9
Fiscal Year
2012
Total Cost
$329,066
Indirect Cost
$114,691
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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 498:325-31
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
Miller, John P; Holcomb, Jennifer; Al-Ramahi, Ismael et al. (2010) Matrix metalloproteinases are modifiers of huntingtin proteolysis and toxicity in Huntington's disease. Neuron 67:199-212
Romero, Eliana; Cha, Guang-Ho; Verstreken, Patrik et al. (2008) Suppression of neurodegeneration and increased neurotransmission caused by expanded full-length huntingtin accumulating in the cytoplasm. Neuron 57:27-40

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