期刊
JOURNAL OF NEUROSCIENCE
卷 38, 期 24, 页码 5478-5494出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3037-17.2018
关键词
ALS; axon degeneration; microfluidic chambers; miRNA; NMJ; Sema3A
资金
- Rosetrees Trust
- IsrALS Foundation
- Israel Science Foundation [561-11, 947/14]
- European Research Council [309377]
- National Institutes of Health [R01-NS44292]
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS044292] Funding Source: NIH RePORTER
Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in amyotrophic lateral sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non-cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR126-5p in presymptomatic ALS male mice models, and an increase in its targets: axon destabilizing Type 3 Semaphorins and their coreceptor Neuropilins. Using compartmentalized in vitro cocultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 blocking antibody. Finally, overexpressing miR126-5p is sufficient to transiently rescue axon degeneration and NMJ disruption both in vitro and in vivo. Thus, we demonstrate a novel mechanism underlying ALS pathology, in which alterations in miR126-5p facilitate a non-cell-autonomous mechanism of motor neuron degeneration in ALS.
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