Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited, fatal neurodegenerative disease that is characterized by progressive motor incoordination and bulbar dysfunction, due primarily to destruction of cerebellar Purkinje cells (eventually the inferior olive and brain stem cranial nuclei are also compromised). Caused by expansion of a translated CAG repeat that encodes a polyglutamine tract in ATAXIN1 (ATXN1) and that alters ATXN1's interactions with its native protein partners, SCA1 shares several features with other more common neurodegenerative proteinopathies such as Parkinson and Alzheimer disease. Two are central to this grant: first, the disease-driving protein is prone to accumulate in neurons; second, there is differential vulnerability to disease pathology among different brain regions despite ubiquitous expression of the disease- driving protein. Over the past four years we have made significant progress investigating the molecular basis of both these features. We discovered that the elevation of steady-state levels of mutant ATXN1, not the aggregation per se, is toxic, and that the toxicity of mutant ATXN1 is primarily due to a gain of its normal functions, particularly those mediated by its native protein partner Capicua-at least in the cerebellum. We therefore explored whether reducing ATXN1 levels mitigates disease. We found that genetic reduction of Capicua (which in turn reduces the activity of both mutant and wild-type ATXN1) mitigates the cerebellar phenotype of SCA1 knock-in mice, as does reduction of 14-3-3e (one of ATXN1's stabilizing binding partners). Our recent unbiased, cross-species, forward genetic screen also revealed that partial inhibition of the RAS- MAPK-MSK1 pathway rescues the cerebellar phenotype. Unfortunately, neither Capicua, 14-3-3, nor ATXN1 itself are viable therapeutic targets at present-but the RAS-MAPK-MSK1 pathway provides a number of druggable targets and, indeed, there are already several drugs used in human patients that inhibit this pathway. In this grant, we propose to evaluate the efficacy and safety of pharmacological inhibitors of the RAS- MAPK-MSK1 pathway (Aim I), as well as screen for additional modifiers that reduce ATXN1 levels in both human cells and our SCA1 Drosophila model (Aim II). Given that SCA1 is a chronic disease, it is likely that combination therapy that mildly inhibits two to three distinct pathways controlling ATXN1 levels will be much safer and better tolerated by patients. We will also investigate region-specific modifications and interactions of ATXN1 to identify those critical for ATXN1 toxicity, using our newly generated mice carrying tagged knock-in Atxn1 alleles for the wild-type and mutant proteins (Aim III). This is not only to find pathways that may mitigate extra-cerebellar symptoms, but to gain further biological insight into ATXN1 functions in both SCA1 pathogenesis and development. The proposed studies stand to identify viable potential therapeutic entry points for SCA1 and provide a strategy and insights relevant to other neurodegenerative proteinopathies.

Public Health Relevance

The burden of neurodegenerative disorders on public health is large and will continue to grow. Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disease for which there is no therapy. The proposed studies will test new potential therapeutics, advance understanding of why neurons degenerate in SCA1, and will reveal new therapeutic entry points, which are essential for the translation of research into clinical treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37NS027699-28
Application #
9114162
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Miller, Daniel L
Project Start
1989-09-01
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
28
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Friedrich, Jillian; Kordasiewicz, Holly B; O'Callaghan, Brennon et al. (2018) Antisense oligonucleotide-mediated ataxin-1 reduction prolongs survival in SCA1 mice and reveals disease-associated transcriptome profiles. JCI Insight 3:
Gennarino, Vincenzo A; Palmer, Elizabeth E; McDonell, Laura M et al. (2018) A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures. Cell 172:924-936.e11
PĂ©rez Ortiz, Judit M; Mollema, Nissa; Toker, Nicholas et al. (2018) Reduction of protein kinase A-mediated phosphorylation of ATXN1-S776 in Purkinje cells delays onset of Ataxia in a SCA1 mouse model. Neurobiol Dis 116:93-105
Orengo, James P; van der Heijden, Meike E; Hao, Shuang et al. (2018) Motor neuron degeneration correlates with respiratory dysfunction in SCA1. Dis Model Mech 11:
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Tan, Qiumin; Brunetti, Lorenzo; Rousseaux, Maxime W C et al. (2018) Loss of Capicua alters early T cell development and predisposes mice to T cell lymphoblastic leukemia/lymphoma. Proc Natl Acad Sci U S A 115:E1511-E1519
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Lu, Hsiang-Chih; Tan, Qiumin; Rousseaux, Maxime W C et al. (2017) Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Nat Genet 49:527-536
Tan, Qiumin; Yalamanchili, Hari Krishna; Park, Jeehye et al. (2016) Extensive cryptic splicing upon loss of RBM17 and TDP43 in neurodegeneration models. Hum Mol Genet 25:5083-5093
Bhat, Neha; Park, Jeehye; Zoghbi, Huda Y et al. (2016) The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development. PLoS One 11:e0166703

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