Ataxin-2 knockdown is neuroprotective via cell-autonomous and non-cell-autonomous mechanisms

Ataxin-2 (Atxn2), a ubiquitously expressed RNA-binding protein, has been implicated in ALS risk, and its silencing represents a promising therapeutic strategy to extend life span and ameliorate symptoms in ALS. Although neuroprotective effects have been shown in several ALS preclinical models, the molecular mechanisms underlying ataxin-2 downregulation neuroprotective effects remain poorly understood. Starting with a global proteomic profiling of the yeast and mouse TDP-43 models, we uncovered that pbp1/ataxin-2 downregulation rewires metabolism to activate alternative cellular pathways for energy production under stress. By combining proteomic profiling insights and functional studies in neural cultures, we further show that ataxin-2 downregulation adjusts metabolism in both cell-autonomous and non cell-autonomous pathways. In neurons, ataxin-2 downregulation activates glycolysis and reductive glutamine carboxylation, while astrocytes provide enhanced support by increasing cholesterol synthesis. Collectively, our data characterize novel cellular pathways to overcome TDP-43 toxicity and establish ataxin-2 as a regulator of adaptive response in brain cells under the conditions of stress.