ATXN2 and proteostasis deficiencies: Importantly, the potential for ataxin-2 as a therapeutic target is supported by several lines of evidence, including that its downregulation in yeast and flies decreases TDP-43-associated toxicity20 and that its genetic ablation in a rodent model of TDP-43 proteinopathy can mitigate pathological features without affecting TDP-43 expression26.