title: Partial loss of Tip60 slows mid-stage neurodegeneration in a spinocerebellar ataxia type 1 (SCA1) mouse model.
abstract: 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. ATXN1 is part of an in vivo complex with retinoid acid receptor-related orphan receptor alpha (Rora) and the acetyltransferase tat-interactive protein 60 kDa (Tip60). ATXN1 and Tip60 interact directly via the ATXN1 and HMG-box protein 1 (AXH) domain of ATXN1. Moreover, the phospho-mimicking Asp amino acid at position 776, previously shown to enhance pathogenesis, increases the ability of ATXN1 to interact with Tip60. Using a genetic approach, the biological relevance of the ATXN1/Tip60 interaction was assessed by crossing ATXN1[82Q] mice with Tip60(+/-)animals. Partial Tip60 loss increased Rora and Rora-mediated gene expression and delayed ATXN1[82]-mediated cerebellar degeneration during mid-stage disease progression. These results suggested a specific, temporal role for Tip60 during disease progression. We also showed that genetic background modulated ATXN1[82Q]-induced phenotypes. Of interest, these latter studies showed that some phenotypes are enhanced on a mixed background while others are suppressed.
authors.affiliation: Institute of Human Genetics and Institute of Translational Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Gehrking
authors.forename: J Michael
authors.initials: JM
authors.lastname: Andresen
authors.forename: Lisa
authors.initials: L
authors.lastname: Duvick
authors.forename: John
authors.initials: J
authors.lastname: Lough
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D016466:CHO Cells; D002874:Chromosome Mapping; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism; D057895:Haploinsufficiency; D051548:Histone Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D015534:Trans-Activators
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D024243:HMGB1 Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D010455:Peptides; D015534:Trans-Activators; C097188:polyglutamine; D051548:Histone Acetyltransferases; C523065:Kat5 protein, mouse; D000074443:Lysine Acetyltransferase 5