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dc.contributor.authorLiang, C.
dc.contributor.authorShao, Q.
dc.contributor.authorChen, R.
dc.date.accessioned2020-04-28T20:12:23Z
dc.date.available2020-04-28T20:12:23Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85083544553&doi=10.1093%2fhmg%2fddaa012&partnerID=40&md5=cc8be5db460282d63f73c1d996743ff9
dc.identifier.urihttp://hdl.handle.net/10713/12667
dc.description.abstractG4C2 repeat expansions in an intron of C9ORF72 cause the most common familial amyotrophic lateral sclerosis and frontotemporal dementia (collectively, C9ALS/FTD). Mechanisms and mediators of C9ALS/FTD pathogenesis remain poorly understood. C9orf72 and Smcr8 form a protein complex. Here, we show that expression of Smcr8, like C9orf72, is reduced in C9ALS/FTD mouse models and patient tissues. Since Smcr8 is highly conserved between human and mouse, we evaluated the effects of Smcr8 downregulation in mice. Smcr8 knockout (KO) mice exhibited motor behavior deficits, which resemble those of C9ALS/FTD mouse models, and displayed axonal swellings in their spinal cords and neuromuscular junctions. These deficits are caused by impaired autophagy-lysosomal functions due to disrupted axonal transport in mutant motor neurons. Consistent with its interaction with C9orf72 and their downregulation in patient tissues, Smcr8 deficiency exacerbated autophagy-lysosomal impairment in C9orf72 KO mice. The disease relevance of Smcr8 downregulation was ref lected by exacerbated axonal swellings and gain of toxicity pathology arising from Smcr8 haploinsufficiency in a mouse model of C9ALS/FTD. Thus, our in vivo studies suggested that Smcr8 deficiency impairs axonal transport dependent autophagy-lysosomal function and exacerbates axonal degeneration and gain of toxicity in C9ALS/FTD mouse models.en_US
dc.description.urihttps://doi.org/10.1093/hmg/ddaa012en_US
dc.language.isoen_USen_US
dc.publisherOxford University Pressen_US
dc.relation.ispartofHuman molecular genetics
dc.subjectC9ALS/FTDen_US
dc.subjectSmcr8en_US
dc.subject.meshFrontotemporal Dementiaen_US
dc.subject.meshAmyotrophic Lateral Sclerosisen_US
dc.subject.meshMice, Knockouten_US
dc.subject.meshModels, Animalen_US
dc.titleSmcr8 deficiency disrupts axonal transport-dependent lysosomal function and promotes axonal swellings and gain of toxicity in C9ALS/FTD mouse modelsen_US
dc.typeArticleen_US
dc.identifier.doi10.1093/hmg/ddaa012
dc.identifier.pmid32057072


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