Serine 776 of ataxin-1 is critical for polyglutamine-induced disease in SCA1 transgenic mice.
Polyglutamine-induced neurodegeneration in transgenic mice carrying the spinocerebellar ataxia type 1 (SCA1) gene is modulated by subcellular distribution of ataxin-1 and by components of the protein folding/degradation machinery. Since phosphorylation is a prominent mechanism by which these processes are regulated, we examined phosphorylation of ataxin-1 and found that serine 776 (S776) was phosphorylated. Residue 776 appeared to affect cellular deposition of ataxin-1[82Q] in that ataxin-1[82Q]-A776 failed to form nuclear inclusions in tissue culture cells. The importance of S776 for polyglutamine-induced pathogenesis was examined by generating ataxin-1[82Q]-A776 transgenic mice. These mice expressed ataxin-1[82Q]-A776 within Purkinje cell nuclei, yet the ability of ataxin-1[82Q]-A776 to induce disease was substantially reduced. These studies demonstrate that polyglutamine tract expansion and localization of ataxin-1 to the nucleus of Purkinje cells are not sufficient to induce disease. We suggest that S776 of ataxin-1 also has a critical role in SCA1 pathogenesis.
Emamian
Effat S
ES
Department of Laboratory Medicine and Pathology, University of Minnesota, Mayo Mail Code 206, Minneapolis, MN 55455, USA.
Kaytor
Michael D
MD
Duvick
Lisa A
LA
Zu
Tao
T
Tousey
Susan K
SK
Zoghbi
Huda Y
HY
Clark
H Brent
HB
Orr
Harry T
HT
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D000067696:Ataxin-1; D000067528:Ataxins; D016466:CHO Cells; D019556:COS Cells; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006224:Cricetinae; D004195:Disease Models, Animal; D005260:Female; D002479:Inclusion Bodies / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011689:Purkinje Cells / Q000378:metabolism* / Q000473:pathology; D012694:Serine / Q000235:genetics / Q000378:metabolism*; D020754:Spinocerebellar Ataxias / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
D000067696:Ataxin-1; D000067528:Ataxins; C000593750:Atxn1 protein, mouse; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C097188:polyglutamine; D012694:Serine