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miRNA malfunction causes spinal motor neuron disease

2010; National Academy of Sciences; Volume: 107; Issue: 29 Linguagem: Inglês

10.1073/pnas.1006151107

1091-6490

Sharon Haramati, Elik Chapnik, Yehezkel Sztainberg, Raya Eilam, Raaya Zwang, Noga Gershoni, Edwina McGlinn, Patrick W. Heiser, Anne‐Marie Wills, Itzhak Wirguin, Lee L. Rubin, Hidemi Misawa, Clifford J. Tabin, Robert H. Brown, Alon Chen, Eran Hornstein,

Amyotrophic Lateral Sclerosis Research

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.