miRNA malfunction causes spinal motor neuron disease

TLDR

Defective RNA metabolism is an emerging mechanism in ALS and other neurodegenerative disorders. The study demonstrates that miRNA activity is essential for long‑term survival of postmitotic spinal motor neurons in vivo. Loss of miRNA processing in spinal motor neurons causes SMA‑like pathology and upregulation of neurofilament heavy subunit, a miR‑9 target that is downregulated in SMA models.

Abstract

Defective RNA metabolism is an emerging mechanism involved in ALS pathogenesis and possibly in other neurodegenerative disorders. Here, we show that microRNA (miRNA) activity is essential for long-term survival of postmitotic spinal motor neurons (SMNs) in vivo. Thus, mice that do not process miRNA in SMNs exhibit hallmarks of spinal muscular atrophy (SMA), including sclerosis of the spinal cord ventral horns, aberrant end plate architecture, and myofiber atrophy with signs of denervation. Furthermore, a neurofilament heavy subunit previously implicated in motor neuron degeneration is specifically up-regulated in miRNA-deficient SMNs. We demonstrate that the heavy neurofilament subunit is a target of miR-9, a miRNA that is specifically down-regulated in a genetic model of SMA. These data provide evidence for miRNA function in SMN diseases and emphasize the potential role of miR-9–based regulatory mechanisms in adult neurons and neurodegenerative states.