The most common dominantly inherited ataxia, Spinocerebellar Ataxia Type 3 (SCA3) is also one of nine neurodegenerative diseases caused by polyglutamine expansion. Although polyglutamine diseases share common features centered on protein misfolding, it is increasingly clear that the pathogenesis of SCA3 and other polyglutamine diseases depends greatly on the specific protein context in which the expansion occurs. The studies proposed here extend our longstanding efforts to understand both the disease mechanisms underlying SCA3 and the normal and disease-related functions of the SCA3 disease protein, a de-ubiquitinating enzyme called ataxin-3. The four proposed aims will investigate key unanswered questions in SCA3 and establish important new model systems.
Aim 1 will test whether ataxin-3 normally suppresses polyglutamine neurodegeneration by virtue of its activity as a ubiquitin chain editing enzyme and whether polyglutamine expansion in ataxin-3 alters this activity.
Aim 2 will address structure-function relationships for this apparently unique enzyme, building on our recent discovery that mono-ubiquitination of ataxin-3 directly enhances its enzymatic activity.
Aim 3 will define the basis of early electrophysiologic changes in the cerebellum of SCA3 transgenic mice and test whether these changes can be modified by channel modulators. Finally, Aim 4 will complete our development of SCA3 knock-in mice, bringing to the research field a genetically precise mouse model of SCA3 that is clearly needed. Together these studies are expected to provide new understanding of the biochemical and cellular processes by which SCA3 occurs and identify potential routes to therapy for this fatal neurodegenerative disease.
Spinocerebellar ataxia type 3 is the most common dominantly inherited ataxia and one of nine diseases caused by polyglutamine expansion. This grant will explore the basis of SCA3 in order that we can ultimately develop therapies for this fatal disease based on a better understanding of disease mechanisms.
|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|
|Zeng, Li; Wang, Bo; Merillat, Sean A et al. (2015) Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3. Neurobiol Dis 82:281-8|
|Faggiano, Serena; Menon, Rajesh P; Kelly, Geoff P et al. (2015) Allosteric regulation of deubiquitylase activity through ubiquitination. Front Mol Biosci 2:2|
|Sanfelice, Domenico; De Simone, Alfonso; Cavalli, Andrea et al. (2014) Characterization of the conformational fluctuations in the Josephin domain of ataxin-3. Biophys J 107:2932-40|
|Tallaksen-Greene, Sara J; Sadagurski, Marianna; Zeng, Li et al. (2014) Differential effects of delayed aging on phenotype and striatal pathology in a murine model of Huntington disease. J Neurosci 34:15658-68|
|Faggiano, Serena; Pastore, Annalisa (2014) The challenge of producing ubiquitinated proteins for structural studies. Cells 3:639-56|
|RÃ¼b, Udo; Hentschel, Matthias; Stratmann, Katharina et al. (2014) Huntington's disease (HD): degeneration of select nuclei, widespread occurrence of neuronal nuclear and axonal inclusions in the brainstem. Brain Pathol 24:247-60|
|Todd, Peter K; Oh, Seok Yoon; Krans, Amy et al. (2013) CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome. Neuron 78:440-55|
|Zeng, Li; Tallaksen-Greene, Sara J; Wang, Bo et al. (2013) The de-ubiquitinating enzyme ataxin-3 does not modulate disease progression in a knock-in mouse model of Huntington disease. J Huntingtons Dis 2:201-15|
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