RORalpha-mediated Purkinje cell development determines disease severity in adult SCA1 mice.
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.
Serra
Heliane G
HG
Institute of Human Genetics, University of Minnesota, Minneapolis, MN 55455, USA.
Duvick
Lisa
L
Zu
Tao
T
Carlson
Kerri
K
Stevens
Sam
S
Jorgensen
Nathan
N
Lysholm
Alana
A
Burright
Eric
E
Zoghbi
Huda Y
HY
Clark
H Brent
HB
Andresen
J Michael
JM
Orr
Harry T
HT
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*
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