Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons

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dc.contributor.authorCastillo, K.
dc.contributor.authorCourt G., Felipe
dc.date.accessioned10-05-2016 15:02
dc.date.available10-05-2016 15:02
dc.date.issued2013
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a fatal motoneuron disease with no current effective treatment. Accumulation of abnormal protein inclusions containing SOD1, TARDBP, FUS, among other proteins, is a pathological hallmark of ALS. Autophagy is the major degradation pathway involved in the clearance of damaged organelles and protein aggregates. Although autophagy has been shown to efficiently degrade ALS-linked mutant protein in cell culture models, several studies suggest that autophagy impairment may also contribute to disease pathogenesis. In this report, we tested the potential use of trehalose, a disaccharide that induces MTOR-independent autophagy, in the development of experimental ALS. Administration of trehalose to mutant SOD1 transgenic mice significantly prolonged life span and attenuated the progression of disease signs. These effects were associated with decreased accumulation of SOD1 aggregates and enhanced motoneuron survival. The protective effects of trehalose were associated with increased autophagy levels in motoneurons. Cell culture experiments demonstrated that trehalose led to mutant SOD1 degradation by autophagy in NSC34 motoneuron cells and also protected primary motoneurons against the toxicity of conditioned media from mutant SOD1 transgenic astrocytes. At the mechanistic level, trehalose treatment led to a significant upregulation in the expression of key autophagy-related genes at the mRNA level including Lc3, Becn1, Sqstm1 and Atg5. Consistent with these changes, trehalose administration enhanced the nuclear translocation of FOXO1, an important transcription factor involved in the activation of autophagy in neurons. This study suggests a potential use of trehalose and enhancers of MTOR-independent autophagy for the treatment of ALS.
dc.format.extent12 páginas
dc.identifier.doi10.4161/auto.25188
dc.identifier.issn1554-8627
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/12290
dc.identifier.urihttps://doi.org/10.4161/auto.25188
dc.identifier.wosidWOS:000327579500005
dc.issue.numero9
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final1320
dc.pagina.inicio1308
dc.revistaAutophagy
dc.rightsacceso abierto
dc.subject.ddc610
dc.subject.deweyMedicina y salud
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.subject.otherEsclerosis lateral amiotrófica
dc.subject.otherEsclerosis lateral amiotrófica -Terapia
dc.subject.otherTrehalosa
dc.titleTrehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons
dc.typeartículo
dc.volumen9
sipa.codpersvinculados8390
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