Partial Tip60 loss slows cerebellar degeneration in a Spinocerebellar Ataxia Type 1 (SCA1) mouse model.
2009-07
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Partial Tip60 loss slows cerebellar degeneration in a Spinocerebellar Ataxia Type 1 (SCA1) mouse model.
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2009-07
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Spinocerebellar ataxia type 1 (SCA1) is one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine tract expansion. In SCA1, the expanded polyglutamine tract is in the ataxin-1 (ATXN1) protein. Increased polyglutamine tract length results in earlier disease onset and greater disease severity, which is largely due to cerebellar Purkinje cell degeneration. ATXN1 is part of an in vivo complex with the nuclear receptor (retinoid acid receptor-related orphan receptor alpha [ROR-alpha]) and acetyltransferase (tat-interactive protein 60 kD [Tip60]). ATXN1 and Tip60 interact directly; however, the significance of this interaction is unclear. To test the effect of partial Tip60 loss on SCA1 disease progression, I developed a mutant ATXN1[82Q]/+:Tip60+/- mouse model. Partial Tip60 loss increased ROR-alpha, Rora, and ROR-alpha-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during midstage disease progression. I also compared ATXN1[82Q]/+ phenotypes between different genetic background strains. Finally in vitro data suggested an ATXN1 polyglutamine length effect on Tip60 acetyltransferase activity. In additional to highlighting genetic background modulation in SCA1 disease, these results suggest a specific temporal role for Tip60 during disease progression and a putative role for Tip60 acetylation in SCA1 disease progression.
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University of Minnesota Ph.D. dissertation. July 2009. Major: Biochemistry, Molecular Biology, and Biophysics. Advisor: Harry T. Orr. 1 computer file (PDF); xii, 137 pages. Ill. (some col.)
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Gehrking, Kristin Marie. (2009). Partial Tip60 loss slows cerebellar degeneration in a Spinocerebellar Ataxia Type 1 (SCA1) mouse model.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/53466.
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