The hereditary ataxias are a group of genetic disorders that share neurological and pathological features, such as loss of balance and coordination, as well as cerebellar neurodegeneration. The ultimate research goal of my laboratory is to understand the cellular and molecular mechanisms that are responsible for cerebellar degeneration in order to develop effective therapeutic interventions for this class of neurodegenerative diseases. To begin to identify these mechanisms, we previously generated a protein-protein interaction network for proteins associated with twenty-three different inherited ataxias. This study and several others suggest that the Wnt-?-catenin signaling pathway may be commonly affected in a subset, if not all, of the hereditary ataxias. However, it has not been determined yet whether Wnt-?-catenin signaling is indeed affected in cerebellum in vivo in the hereditary ataxias or whether the altered activity of the Wnt-?-catenin signaling pathway is responsible for the cerebellar neurodegeneration. To address these questions, we use spinocerebellar ataxia type 1 (SCA1) as a prototype of hereditary cerebellar ataxias. SCA1 is a dominantly inherited neurodegenerative disorder characterized by progressive degeneration of cerebellar Purkinje cells (PCs), brainstem cranial nerve nuclei and inferior olive nuclei, and spinocerebellar tracts. SCA1 is caused by a glutamine expansion in ATAXIN1 (ATXN1). The preliminary data presented in this application clearly show that the Wnt-?-catenin signaling pathway is functionally active in normal PCs in the adult cerebellum in mice and this activation is strongly enhanced in PCs in SCA1 mice. We also provide evidence that the enhanced activation of Wnt-?-catenin signaling in SCA1-affected neurons, such as cerebellar PCs and the inferior olive, results in cerebellar PC atrophy and/or degeneration in adults. These data strongly support the idea that Wnt- ?-catenin signaling may have a crucial role in the physiology of the adult cerebellum and/or in cerebellar neurodegeneration. Here, we hypothesize that the disease-causing mutant ATXN1 protein strongly activates Wnt-?-catenin signaling beyond the normal level in SCA1 mice, and that this upregulation is sufficient to cause PC dysfunction and degeneration. To investigate this hypothesis we will perform the following specific studies: 1) Explore the role of Wnt-?-catenin signaling in PC function/survival in the normal adult cerebellum;2) Identify the molecular mechanisms by which polyglutamine-expanded mutant ATXN1 activates Wnt-?-catenin signaling;3) Determine the in vivo relevance of enhanced activation of Wnt-?-catenin signaling in SCA1 pathogenesis. The knowledge gained from the studies proposed in this application will advance our understanding of the cellular and molecular mechanisms underlying cerebellar neurodegeneration and will suggest new therapeutic interventions aimed at reducing the burden of these devastating diseases.

Public Health Relevance

The burden of neurodegenerative diseases is large, yet no effective therapeutics exists for a majority of these devastating disorders. The studies outlined i this application will allow us to determine the key pathogenic pathways in cerebellar neurodegeneration, and may also lead to the development of effective therapeutics.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gwinn, Katrina
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Yale University
Schools of Medicine
New Haven
United States
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Driessen, Terri M; Lee, Paul J; Lim, Janghoo (2018) Molecular pathway analysis towards understanding tissue vulnerability in spinocerebellar ataxia type 1. Elife 7:
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