miRNA malfunction causes spinal motor neuron disease.
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.
Haramati
Sharon
S
Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel.
Chapnik
Elik
E
Sztainberg
Yehezkel
Y
Eilam
Raya
R
Zwang
Raaya
R
Gershoni
Noga
N
McGlinn
Edwina
E
Heiser
Patrick W
PW
Wills
Anne-Marie
AM
Wirguin
Itzhak
I
Rubin
Lee L
LL
Misawa
Hidemi
H
Tabin
Clifford J
CJ
Brown
Robert
R
Chen
Alon
A
Hornstein
Eran
E
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009043:Motor Activity / Q000502:physiology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009121:Muscle Denervation; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000503:physiopathology*; D016900:Neurofilament Proteins / Q000378:metabolism; D021122:Protein Subunits / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D016019:Survival Analysis
C551804:MIRN9 microRNA, mouse; D035683:MicroRNAs; D016900:Neurofilament Proteins; D021122:Protein Subunits; D043244:Ribonuclease III