title: RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.
abstract: Spinocerebellar ataxia type 1 (SCA1) is one of nine inherited, typically adult onset, polyglutamine neurodegenerative diseases. To examine whether development impacts SCA1, we used a conditional transgenic mouse model of SCA1 to delay the postnatal expression of mutant ATXN1 until after completion of cerebellar development. Delayed postnatal expression of mutant ATXN1 led to a substantial reduction in severity of disease in adults in comparison with early postnatal gene expression. This was linked to a destabilization of RORalpha, a transcription factor critical for cerebellar development. In SCA1 mice, there was a depletion of RORalpha and a reduction in expression of genes controlled by RORalpha. Partial loss of RORalpha enhanced mutant ATXN1 pathogenicity. Additionally, evidence points to the existence of a complex containing ATXN1, RORalpha, and the RORalpha coactivator Tip60. These studies indicate RORalpha and Tip60 have a role in SCA1 and suggest a mechanism by which compromising cerebellar development contributes to severity of neurodegeneration in an adult.
authors.affiliation: Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Heliane G
authors.initials: HG
authors.lastname: Serra
authors.forename: Lisa
authors.initials: L
authors.lastname: Duvick
authors.forename: Tao
authors.initials: T
authors.lastname: Zu
authors.forename: Kerri
authors.initials: K
authors.lastname: Carlson
authors.forename: Sam
authors.initials: S
authors.lastname: Stevens
authors.forename: Nathan
authors.initials: N
authors.lastname: Jorgensen
authors.forename: Alana
authors.initials: A
authors.lastname: Lysholm
authors.forename: Eric
authors.initials: E
authors.lastname: Burright
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
authors.forename: H Brent
authors.initials: HB
authors.lastname: Clark
authors.forename: J Michael
authors.initials: JM
authors.lastname: Andresen
authors.forename: Harry T
authors.initials: HT
authors.lastname: Orr
mesh_terms: D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D019556:COS Cells; D002522:Chlorocebus aethiops; D018450:Disease Progression; D015536:Down-Regulation / Q000235:genetics; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011689:Purkinje Cells / Q000166:cytology* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000378:metabolism*; D015534:Trans-Activators / Q000172:deficiency / Q000378:metabolism*
chemical_list: C000593749:ATXN1 protein, human; D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D050505:Mutant Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D012333:RNA, Messenger; C539738:RORA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D051548:Histone Acetyltransferases