MiR-105 and miR-9 regulate the mRNA stability of neuronal intermediate filaments. Implications for the pathogenesis of amyotrophic lateral sclerosis (ALS)

Intermediate filament aggregation within motor neurons is a hallmark of ALS pathogenesis. Changes to intermediate filament stoichiometry due to altered mRNA steady-state levels of NEFL, PRPH and INA is thought to drive protein aggregation, yet the exact cause of these changes is unknown. MicroRNAs (miRNAs)-master regulators of gene expression-are largely dysregulated within ALS motor neurons and are known to be major contributors to the disease. We show that miR-105 and miR-9 are down-regulated within the spinal cord of ALS patients and target NEFL, PRPH and INA 3'UTRs to regulate gene expression. Further, both miR-105 and miR-9 were observed to regulate the mRNA stability of these three intermediate filaments endogenously within a neuronal-derived cell line. Our data demonstrates that miR-105 and miR-9 can regulate the mRNA stability of these key intermediate filaments and thus potentially contribute to the pathogenesis of intermediate filament inclusions in ALS.