Modeling amyotrophic lateral sclerosis through Ataxin-2 pathology

Ataxin-2 (ATXN2) is a stress-responsive RNA-binding protein that modulates global translation. Expansion of its polyQ domain due to genomic CAG repeat expansions underlies multiple maladies, as monogenic cause for spinocerebellar ataxia type 2 (SCA2), or polygenic risk factor for Parkinsonism syndromes and amyotrophic lateral sclerosis (ALS), due to progressive protein aggregation. Discovery of ATXN2 colocalization in stress granules (SGs) with known ALS proteins, such as TDP-43 and FUS, and the observation that ATXN2 deficiency strongly extends the lifespan of TDP-43-mutant mice, showed its value as a therapeutic target. Thus, a knock-in mouse model of ATXN2 pathology (Atxn2-CAG100-KIN) was generated with 100 CAG repeats inserted into the endogenous Atxn2 locus in murine genome. Preserving the expression pattern throughout the body and avoiding the prominent artifacts of transgenic overexpression, this mouse provides an authentic tool to dissect the molecular alterations spatiotemporally in accurate manner during its lifespan of 9–12 months. As relatively well-established hallmark of ALS, deduced from postmortem patient histology, TDP-43 protein aggregates were observed in spinal cord motor neurons. Moreover, selective dysregulations, e.g., of RIPK1, Grn, Hnrnpa2b1, and Kif5a, mirrored ALS tissue pathology. Importantly, the pathogenic expansion knock-in can be converted into the neuroprotective Atxn2 knock-out by Tamoxifen-Cre technology, so this mouse represents a unique tool to dissect benefits of the recently developed anti-sense oligonucleotide technology targeting Atxn2, for the preventive treatment of ALS and SCA2.