Sertraline treatment prevents motor dysfunction in a Huntington's disease mouse model and functional decline in patients.

Abstract

Molecular alterations underlying Huntington's disease (HD) are not fully elucidated and no curative therapies are available. We have described that increased translation efficiency participates in the motor symptoms in the R6/1 HD mouse model. Here, we evaluated whether sertraline, a widely used antidepressant drug, that modulates translation in cancer cells, could ameliorate motor and cognitive symptoms in HD. We also investigated if alterations in translation efficiency occur in fibroblasts from HD patients and serve as a possible biomarker. As an index of translation efficiency levels, we analyzed puromycin incorporation and phosphorylated 4E-BP1 levels in striatal primary cultures and striatum from R6/1 mice, and in HD patients' fibroblasts, with or without sertraline treatment. Motor learning and coordination were analyzed in treated mice by accelerating rotarod, balance beam and vertical pole tests. Clinical data from the Enroll-HD dataset were analyzed to evaluate the potential effects of sertraline treatment in the disease progression. We report that sertraline treatment: 1) modulates translation efficiency in striatal primary neurons expressing mutant huntingtin; 2) prevents motor dysfunction in R6/1 mice and normalizes translation efficiency in the striatum, and 3) delays the decline in functional performance of HD patients. Moreover, puromycin incorporation is increased in fibroblasts from HD patients in a CAG length-dependent manner and is modulated by sertraline treatment. Altogether, our results suggest sertraline as a promising candidate for HD clinical trials to slow down disease progression and that puromycin incorporation in fibroblasts could serve as a pharmacological biomarker for certain treatments.