Serine 776 of Ataxin-1 Is Critical for Polyglutamine-Induced Disease in SCA1 Transgenic Mice

Abstract

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.

Imperfect CAG Repeats Form Diverse Structures in SCA1 Transcripts

“…2C). Only at the temperature of 70°C and higher the structure formed by the helices H4 and 14 12-1-1-1-14 ⌬ ϭ Ϫ2 29 (CAG) 16 CAUCAGCAU (CAG) 10 16-1-1-1-10 ⌬ ϭ ϩ6 (CAG) 12 CAU (CAG) 16 12-1-16 ⌬ ϭ Ϫ4 30 (CAG) 12 CAUCAGCAU (CAG) 15 12-1-1-1-15 ⌬ ϭ Ϫ3 (CAG) 13 CAUCAGCAU (CAG) 14 13-1-1-1-14 ⌬ ϭ Ϫ1 31 (CAG) 11 CAUCAGCAUCAGCAU (CAG) 15 11-1-1-1-1-1-15 ⌬ ϭ Ϫ4 32 (CAG) 14 CAUCAGCAU (CAG) 15 14-1-1-1-15 ⌬ ϭ Ϫ1 (CAG) 12 CAUCAGCAU (CAG) 17 12- H3 was melted and all internucleotide bonds of that region showed similar reactivity. The structures formed by the repeats containing asymmetrically located interruptions are somewhat different (Fig.…”

“…It may interfere with neuronal transcription by interacting with specific transcription factors in a poly-Q-dependent manner and induce apoptotic cell death (13). On the other hand, recent studies revealed the importance of the ataxin-1-specific sequence context for the protein function and showed that even the high level expression of an expanded poly-Q tract protein in the nucleus may be insufficient to cause disease (14). In this light the RNA-mediated mechanisms of pathogenesis, similar to those proposed for DM (15) and FXTAS (16 -18) were also considered for polyglutamine diseases (17)(18)(19)(20)(21).…”

Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model

“…Several animal models have been generated and investigated (Burright et al, 1995;Fernandez-Funez et al, 2000;Watase et al, 2002;Emamian et al, 2003;Chen et al, 2003) in order to understand the processes that underlie the onset and progression of SCA1. Data show that mutant ATAXIN1 protein levels have a key role in modulating disease pathogenesis.…”

Mutant huntingtin impairs Ku70-mediated DNA repair

“…In the case of mutant Atx1, normal binding partners, including Capicua and RBM17, play critical roles in the pathology through gain of function or loss of function (Emamian et al, 2003;Lam et al, 2006;Lim et al, 2008). In our current analyses with cellular and Drosophila SCA1 models, the rescue effects of Ku70 on the SCA1 pathology were smaller than that on the HD pathology (unpublished data).…”