MicroRNA-183-5p is stress-inducible and protects neurons against cell death in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons. A fundamental pathogenesis of ALS is the prolonged cell stress in neurons, which is caused by either accumulation of protein aggregates or reactive oxygen species. However, the mechanistic link between stress sensing and cell death is unsettled. Here, we identify that miR-183-5p, a neuron-enriched miRNA, couples stress sensing and cell death programming in ALS. miR-183-5p is immediately induced by hydrogen peroxide, tunicamycin or TNF-α in neurons. The overexpression of miR-183-5p increases neuron survival under stress conditions, whereas its knockdown causes neuron death. miR-183-5p coordinates apoptosis and necroptosis pathways by directly targeting PDCD4 and RIPK3, and thus protects neurons against cell death under stress conditions. The consistent reduction of miR-183-5p in ALS patients and mouse models enhances the notion that miR-183-5p is a central regulator of motor neuron survival under stress conditions. Our study supplements current understanding of the mechanistic link between cell stress and death/survival, and provides novel targets for clinical interventions of ALS.

Keywords: miR-183-5p; amyotrophic lateral sclerosis; cell death; cell stress.