Cargando…
Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice
Parkinson’s disease is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and motor symptoms, but also by non-motor symptoms. Metabolic abnormalities including body weight loss have been reported in patients and could...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176013/ https://www.ncbi.nlm.nih.gov/pubmed/30333721 http://dx.doi.org/10.3389/fnmol.2018.00321 |
_version_ | 1783361619256934400 |
---|---|
author | Cuvelier, Elodie Méquinion, Mathieu Leghay, Coline Sibran, William Stievenard, Aliçia Sarchione, Alessia Bonte, Marie-Amandine Vanbesien-Mailliot, Christel Viltart, Odile Saitoski, Kevin Caron, Emilie Labarthe, Alexandra Comptdaer, Thomas Semaille, Pierre Carrié, Hélène Mutez, Eugénie Gressier, Bernard Destée, Alain Chartier-Harlin, Marie-Christine Belarbi, Karim |
author_facet | Cuvelier, Elodie Méquinion, Mathieu Leghay, Coline Sibran, William Stievenard, Aliçia Sarchione, Alessia Bonte, Marie-Amandine Vanbesien-Mailliot, Christel Viltart, Odile Saitoski, Kevin Caron, Emilie Labarthe, Alexandra Comptdaer, Thomas Semaille, Pierre Carrié, Hélène Mutez, Eugénie Gressier, Bernard Destée, Alain Chartier-Harlin, Marie-Christine Belarbi, Karim |
author_sort | Cuvelier, Elodie |
collection | PubMed |
description | Parkinson’s disease is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and motor symptoms, but also by non-motor symptoms. Metabolic abnormalities including body weight loss have been reported in patients and could precede by several years the emergence of classical motor manifestations. However, our understanding of the pathophysiological mechanisms underlying body weight loss in PD is limited. The present study investigated the links between alpha-synuclein accumulation and energy metabolism in transgenic mice overexpressing Human wild-type (WT) alpha-synuclein under the Thy1 promoter (Thy1-aSYN mice). Results showed that Thy1-aSYN mice gained less body weight throughout life than WT mice, with significant difference observed from 3 months of age. Body composition analysis of 6-month-old transgenic animals showed that body mass loss was due to lower adiposity. Thy1-aSYN mice displayed lower food consumption, increased spontaneous activity, as well as a reduced energy expenditure compared to control mice. While no significant change in glucose or insulin responses were observed, Thy1-aSYN mice had significantly lower plasmatic levels of insulin and leptin than control animals. Moreover, the pathological accumulation of alpha-synuclein in the hypothalamus of 6-month-old Thy1-aSYN mice was associated with a down-regulation of the phosphorylated active form of the signal transducer and activator of transcription 3 (STAT3) and of Rictor (the mTORC2 signaling pathway), known to couple hormonal signals with the maintenance of metabolic and energy homeostasis. Collectively, our results suggest that (i) metabolic alterations are an important phenotype of alpha-synuclein overexpression in mice and that (ii) impaired STAT3 activation and mTORC2 levels in the hypothalamus may underlie the disruption of feeding regulation and energy metabolism in Thy1-aSYN mice. |
format | Online Article Text |
id | pubmed-6176013 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-61760132018-10-17 Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice Cuvelier, Elodie Méquinion, Mathieu Leghay, Coline Sibran, William Stievenard, Aliçia Sarchione, Alessia Bonte, Marie-Amandine Vanbesien-Mailliot, Christel Viltart, Odile Saitoski, Kevin Caron, Emilie Labarthe, Alexandra Comptdaer, Thomas Semaille, Pierre Carrié, Hélène Mutez, Eugénie Gressier, Bernard Destée, Alain Chartier-Harlin, Marie-Christine Belarbi, Karim Front Mol Neurosci Neuroscience Parkinson’s disease is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and motor symptoms, but also by non-motor symptoms. Metabolic abnormalities including body weight loss have been reported in patients and could precede by several years the emergence of classical motor manifestations. However, our understanding of the pathophysiological mechanisms underlying body weight loss in PD is limited. The present study investigated the links between alpha-synuclein accumulation and energy metabolism in transgenic mice overexpressing Human wild-type (WT) alpha-synuclein under the Thy1 promoter (Thy1-aSYN mice). Results showed that Thy1-aSYN mice gained less body weight throughout life than WT mice, with significant difference observed from 3 months of age. Body composition analysis of 6-month-old transgenic animals showed that body mass loss was due to lower adiposity. Thy1-aSYN mice displayed lower food consumption, increased spontaneous activity, as well as a reduced energy expenditure compared to control mice. While no significant change in glucose or insulin responses were observed, Thy1-aSYN mice had significantly lower plasmatic levels of insulin and leptin than control animals. Moreover, the pathological accumulation of alpha-synuclein in the hypothalamus of 6-month-old Thy1-aSYN mice was associated with a down-regulation of the phosphorylated active form of the signal transducer and activator of transcription 3 (STAT3) and of Rictor (the mTORC2 signaling pathway), known to couple hormonal signals with the maintenance of metabolic and energy homeostasis. Collectively, our results suggest that (i) metabolic alterations are an important phenotype of alpha-synuclein overexpression in mice and that (ii) impaired STAT3 activation and mTORC2 levels in the hypothalamus may underlie the disruption of feeding regulation and energy metabolism in Thy1-aSYN mice. Frontiers Media S.A. 2018-10-02 /pmc/articles/PMC6176013/ /pubmed/30333721 http://dx.doi.org/10.3389/fnmol.2018.00321 Text en Copyright © 2018 Cuvelier, Méquinion, Leghay, Sibran, Stievenard, Sarchione, Bonte, Vanbesien-Mailliot, Viltart, Saitoski, Caron, Labarthe, Comptdaer, Semaille, Carrié, Mutez, Gressier, Destée, Chartier-Harlin and Belarbi. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Cuvelier, Elodie Méquinion, Mathieu Leghay, Coline Sibran, William Stievenard, Aliçia Sarchione, Alessia Bonte, Marie-Amandine Vanbesien-Mailliot, Christel Viltart, Odile Saitoski, Kevin Caron, Emilie Labarthe, Alexandra Comptdaer, Thomas Semaille, Pierre Carrié, Hélène Mutez, Eugénie Gressier, Bernard Destée, Alain Chartier-Harlin, Marie-Christine Belarbi, Karim Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice |
title | Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice |
title_full | Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice |
title_fullStr | Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice |
title_full_unstemmed | Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice |
title_short | Overexpression of Wild-Type Human Alpha-Synuclein Causes Metabolism Abnormalities in Thy1-aSYN Transgenic Mice |
title_sort | overexpression of wild-type human alpha-synuclein causes metabolism abnormalities in thy1-asyn transgenic mice |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176013/ https://www.ncbi.nlm.nih.gov/pubmed/30333721 http://dx.doi.org/10.3389/fnmol.2018.00321 |
work_keys_str_mv | AT cuvelierelodie overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT mequinionmathieu overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT leghaycoline overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT sibranwilliam overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT stievenardalicia overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT sarchionealessia overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT bontemarieamandine overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT vanbesienmailliotchristel overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT viltartodile overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT saitoskikevin overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT caronemilie overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT labarthealexandra overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT comptdaerthomas overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT semaillepierre overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT carriehelene overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT mutezeugenie overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT gressierbernard overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT desteealain overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT chartierharlinmariechristine overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice AT belarbikarim overexpressionofwildtypehumanalphasynucleincausesmetabolismabnormalitiesinthy1asyntransgenicmice |