Modulation of ATXN1 S776 phosphorylation reveals the importance of allele-specific targeting in SCA1

Disrupting ATXN1 Nuclear Localization in a Knock-in SCA1 Mouse Model Improves a Spectrum of SCA1-Like Phenotypes and their Brain Region Associated Transcriptomic Profiles

“…Thus, the NLS mutation had a dramatic impact on survival. Notably, this relative extension in lifespan is the largest observed resulting from any intervention performed by our group or collaborators (Friedrich et al, 2018;Nitschke et al, 2021;Coffin et al, unpublished data).…”

“…Mutation of the ATXN1[175Q] NLS nearly doubled the lifespan of Atxn1(175Q)K772T mice relative to Atxn1(175Q) mice (Figure 2C). This extension is, to our knowledge, the most substantial of any survival study results seen in animal models of SCA1 (Friedrich et al, 2018;Nitschke et al, 2021;Coffin et al, unpublished data). Thus, proper nuclear localization plays a critical role in the pathological dysfunction that underlies the premature lethality of Atxn1(175Q) mice.…”

Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

“…For example, decrease of amyloid precursor protein (APP), α-syn, and HTT rescues phenotypes of AD, PD, and HD in mice, respectively (5)(6)(7). This is also true for SCA1, as decreasing ATXN1 rescues disease phenotypes in mice (13)(14)(15), but specifically reducing mutant ATXN1 is more effective than targeting both WT and mutant ATXN1 (18). Because ATXN1 does not have enzymatic activity, it is not a feasible target for small molecule inhibition.…”

“…Patients with SCA1 experience motor deficits and bulbar dysfunction, leading to difficulties in breathing and swallowing. Although previous work has shown that reducing both WT and mutant ATXN1 protein levels can rescue disease phenotypes in an SCA1 mouse model (13)(14)(15), it is critical to reduce mutant ATXN1 specifically for the following reasons: (1) loss of WT ATXN1 can potentiate AD by increasing Aβ deposition (16); (2) WT ATXN1 is protective for SCA1 (17); (3) selective reduction of mutant ATXN1 is more effective in rescuing disease phenotype than targeting both mutant and WT protein (18). Therefore, identifying mutant ATXN1-specific regulators is critical to understanding the molecular pathogenesis of SCA1 and to finding more effective therapeutic targets for the disease.…”

Reduction of mutant ATXN1 rescues premature death in a conditional SCA1 mouse model

“…When this mutation was introduced specifically on the polyglutamine-expanded ATXN1, there was a partial rescue of SCA1 pathology (39). However, when both the wildtype and polyglutamine-expanded alleles contained the phospho-dead mutation at S776 the mice continued to develop characteristic SCA1 pathology at nearly the same pace as unmodified SCA1 mice (39).…”