title: Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons.
abstract: Amyotrophic 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.
authors.affiliation: Biomedical Neuroscience Institute; Faculty of Medicine; University of Chile; Santiago, Chile; Center for Molecular Studies of the Cell; Program of Cellular and Molecular Biology; Institute of Biomedical Sciences; University of Chile; Santiago, Chile.
authors.forename: Karen
authors.initials: K
authors.lastname: Castillo
authors.forename: Melissa
authors.initials: M
authors.lastname: Nassif
authors.forename: Vicente
authors.initials: V
authors.lastname: Valenzuela
authors.forename: Fabiola
authors.initials: F
authors.lastname: Rojas
authors.forename: Soledad
authors.initials: S
authors.lastname: Matus
authors.forename: Gabriela
authors.initials: G
authors.lastname: Mercado
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Court
authors.forename: Brigitte
authors.initials: B
authors.lastname: van Zundert
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects; D018450:Disease Progression; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008136:Longevity / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020836:Protein Structure, Quaternary; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000473:pathology; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014199:Trehalose / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D014199:Trehalose; D013482:Superoxide Dismutase
keywords: amyotrophic lateral sclerosis; autophagy; copper-zinc superoxide dismutase 1; protein aggregation; trehalose