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

Karen Castillo, Melissa Nassif, Vicente Valenzuela, Fabiola Rojas, Soledad Matus, Gabriela Mercado, Felipe A. Court, Brigitte Van Zundert, Claudio Hetz

Resultado de la investigación: Article

160 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)1308-1320
Número de páginas13
PublicaciónAutophagy
Volumen9
N.º9
DOI
EstadoPublished - 1 ene 2013

Huella dactilar

Trehalose
Autophagy
Amyotrophic Lateral Sclerosis
Motor Neurons
Cell Culture Techniques
Disaccharides
Mutant Proteins
Conditioned Culture Medium
Astrocytes
Organelles
Transgenic Mice
Disease Progression
Proteins
Transcription Factors
Up-Regulation
Neurons
Messenger RNA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Citar esto

Castillo, K., Nassif, M., Valenzuela, V., Rojas, F., Matus, S., Mercado, G., ... Hetz, C. (2013). Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy, 9(9), 1308-1320. https://doi.org/10.4161/auto.25188
Castillo, Karen ; Nassif, Melissa ; Valenzuela, Vicente ; Rojas, Fabiola ; Matus, Soledad ; Mercado, Gabriela ; Court, Felipe A. ; Van Zundert, Brigitte ; Hetz, Claudio. / Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. En: Autophagy. 2013 ; Vol. 9, N.º 9. pp. 1308-1320.
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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.",
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Castillo, K, Nassif, M, Valenzuela, V, Rojas, F, Matus, S, Mercado, G, Court, FA, Van Zundert, B & Hetz, C 2013, 'Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons', Autophagy, vol. 9, n.º 9, pp. 1308-1320. https://doi.org/10.4161/auto.25188

Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. / Castillo, Karen; Nassif, Melissa; Valenzuela, Vicente; Rojas, Fabiola; Matus, Soledad; Mercado, Gabriela; Court, Felipe A.; Van Zundert, Brigitte; Hetz, Claudio.

En: Autophagy, Vol. 9, N.º 9, 01.01.2013, p. 1308-1320.

Resultado de la investigación: Article

TY - JOUR

T1 - Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons

AU - Castillo, Karen

AU - Nassif, Melissa

AU - Valenzuela, Vicente

AU - Rojas, Fabiola

AU - Matus, Soledad

AU - Mercado, Gabriela

AU - Court, Felipe A.

AU - Van Zundert, Brigitte

AU - Hetz, Claudio

PY - 2013/1/1

Y1 - 2013/1/1

N2 - 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.

AB - 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.

KW - Amyotrophic lateral sclerosis

KW - Autophagy

KW - Copper-zinc superoxide dismutase 1

KW - Protein aggregation

KW - Trehalose

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U2 - 10.4161/auto.25188

DO - 10.4161/auto.25188

M3 - Article

C2 - 23851366

AN - SCOPUS:84884294596

VL - 9

SP - 1308

EP - 1320

JO - Autophagy

JF - Autophagy

SN - 1554-8627

IS - 9

ER -

Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G y otros. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy. 2013 ene 1;9(9):1308-1320. https://doi.org/10.4161/auto.25188