Riluzole does not ameliorate disease caused by cytoplasmic TDP‐43 in a mouse model of amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS, and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP‐43), and understanding the effects of riluzole in models that closely recapitulate TDP‐43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in female transgenic mice that inducibly express nuclear localisation sequence (NLS)‐deficient human TDP‐43 in neurons (NEFH‐tTA/tetO‐hTDP‐43ΔNLS, ‘rNLS8’, mice). Riluzole treatment from the first day of hTDP‐43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP‐43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS8 mice, riluzole did not ameliorate this disease‐associated molecular phenotype. Likewise, riluzole did not alter the disease‐associated atrophy of hindlimb muscle in rNLS8 mice. Finally, riluzole treatment beginning after disease onset in rNLS8 mice similarly had no effect on progression of late‐stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre‐type changes reminiscent of ALS in female rNLS8 mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways related to accumulation of TDP‐43 pathology may be needed to develop better treatments for ALS. Riluzole is the most widely used pharmacological therapy for amyotrophic lateral sclerosis (ALS). Here, in the rNLS8 TDP‐43 mouse model that recapitulates key features of human ALS, we show that riluzole is ineffective at ameliorating disease pathologies including phosphorylation of TDP‐43, glutamate receptor loss in the cortex and hindlimb muscle atrophy. Likewise, riluzole does not prevent motor function decline or extend survival of rNLS8 mice.