Metformin treatment reduces motor and neuropsychiatric phenotypes in the zQ175 mouse model of Huntington disease

Fecha de publicación: 05/06/2019

Autores de IIS La Fe

María Dolores Sequedo Pérez

Autor
José María Millán Salvador

Autor
Rafael Vázquez Manrique

Autor

Participantes ajenos a IIS La Fe

Sanchis, A
Garcia-Gimeno, MA
Canada-Martinez, AJ
Sanz, P

Grupos

Biomedicina Molecular, Celular y Genómica

Leader

José María Millán Salvador
Unidad mixta de investigación en enfermedades raras (CIPF)

Leader

José María Millán Salvador

Abstract

Huntington disease is a neurodegenerative condition for which there is no cure to date. Activation of AMP-activated protein kinase has previously been shown to be beneficial in in vitro and in vivo models of Huntington's disease. Moreover, a recent cross-sectional study demonstrated that treatment with metformin, a well-known activator of this enzyme, is associated with better cognitive scores in patients with this disease. We performed a preclinical study using metformin to treat phenotypes of the zQ175 mouse model of Huntington disease. We evaluated behavior (motor and neuropsychiatric function) and molecular phenotypes (aggregation of mutant huntingtin, levels of brain-derived neurotrophic factor, neuronal inflammation, etc.). We also used two models of polyglutamine toxicity in Caenorhabditis elegans to further explore potential mechanisms of metformin action. Our results provide strong evidence that metformin alleviates motor and neuropsychiatric phenotypes in zQ175 mice. Moreover, metformin intake reduces the number of nuclear aggregates of mutant huntingtin in the striatum. The expression of brain-derived neurotrophic factor, which is reduced in mutant animals, is partially restored in metformin-treated mice, and glial activation in mutant mice is reduced in metformin-treated animals. In addition, using worm models of polyglutamine toxicity, we demonstrate that metformin reduces polyglutamine aggregates and restores neuronal function through mechanisms involving AMP-activated protein kinase and lysosomal function. Our data indicate that metformin alleviates the progression of the disease and further supports AMP-activated protein kinase as a druggable target against Huntington's disease.

Datos de la publicación

ISSN/ISSNe:: 1226-3613, 2092-6413
Tipo:: Article
Páginas:: 65-65
DOI:: 10.1038/s12276-019-0264-9
Factor de Impacto:: 2,136 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Sanchis, A:: Instituto de Investigación. Hosp Univ & Politecn La Fe, Hlth Res Inst La Fe, Res Grp Mol Cellular & Genom Biomed, Valencia, Spain
Garcia-Gimeno, MA:: Univ Politecn Valencia, ETSIAMN, Dept Biotechnol, Valencia, Spain
Canada-Martinez, AJ:: Instituto de Investigación. Hosp Univ & Politecn La Fe, Hlth Res Inst La Fe, Stat Unit, Valencia, Spain
Sequedo, MD:: Instituto de Investigación. Hosp Univ & Politecn La Fe, Hlth Res Inst La Fe, Res Grp Mol Cellular & Genom Biomed, Valencia, Spain

CIBER Enfermedades Raras CIBERER, Madrid, Spain
Millan, JM:: Instituto de Investigación. Hosp Univ & Politecn La Fe, Hlth Res Inst La Fe, Res Grp Mol Cellular & Genom Biomed, Valencia, Spain

CIBER Enfermedades Raras CIBERER, Madrid, Spain
Sanz, P:: CIBER Enfermedades Raras CIBERER, Madrid, Spain

CSIC, Inst Biomed Valencia, Valencia, Spain
Vazquez-Manrique, RP:: Instituto de Investigación. Hosp Univ & Politecn La Fe, Hlth Res Inst La Fe, Res Grp Mol Cellular & Genom Biomed, Valencia, Spain

CIBER Enfermedades Raras CIBERER, Madrid, Spain

Keywords

ACTIVATED PROTEIN-KINASE; TAIL SUSPENSION TEST; NEURONS; DYSFUNCTION; AUTOPHAGY; BDNF; QUANTIFICATION; ABNORMALITIES; VULNERABILITY; MECHANISMS

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