Ataxin-2 downregulation rewires neuronal and astrocytic metabolism to protect against TDP-43 toxicity.

Reducing ataxin-2 activates stress-adaptive metabolic pathways in neurons and astrocytes, providing broad protection against TDP-43 toxicity in ALS models.

• Why it matters: Understanding how ataxin-2 confers neuroprotection could reveal new therapeutic strategies for ALS, as its mechanisms remain poorly understood and it influences TDP-43 toxicity.
• What they did: Using proteomic profiling in yeast and mouse TDP-43 models, the study examined effects of ataxin-2 reduction, finding activation of glycolysis and glutamine carboxylation in neurons and cholesterol biosynthesis in astrocytes.
• The result: Ataxin-2 downregulation fully rescues neuronal survival only when both mechanisms are engaged in neuron-astrocyte co-cultures, and it protects against both gain- and loss-of-function TDP-43 toxicity, broadening its therapeutic potential.