Overexpression of wild-type human alpha-synuclein causes metabolism abnormalities in thy1-asyn transgenic mice

Autor: Cuvelier, Elodie, Mequinion, Mathieu, Leghay, Coline, Sibran, William, Stievenard, Alicia, Sarchione, Alessia, Bonte, Marie-Amandine, Vanbesien, Christel, Viltart, Odile, Saitoski, Kevin, Caron, Emilie, Labarthe, Alexandra, Comptdaer, Thomas, Semaille, Pierre, Carrie, Helene, Mutez, Eugenie, Gressier, Bernard, Destée, Alain, Chartier Harlin, Marie-Christine, Belarbi, Karim-Ali
Přispěvatelé: Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Centre de Psychiatrie et Neurosciences (U894), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université de Lille, LillOA, CHU Lille, Inserm, Université de Lille, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc) - U1172, Lille Neurosciences & Cognition (LilNCog) - U 1172, Institut de psychiatrie et neurosciences de Paris [IPNP - U1266 Inserm - Paris Descartes], Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365, Groupe de Recherche sur les formes Injectables et les Technologies Associées - ULR 7365 [GRITA], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Lille Neurosciences & Cognition - U 1172 [LilNCog], Université Paris Descartes - Paris 5 [UPD5]
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Frontiers in Molecular Neuroscience
Frontiers in Molecular Neuroscience, 2018, 11, pp.321. ⟨10.3389/fnmol.2018.00321⟩
Frontiers in Molecular Neuroscience, Vol 11 (2018)
Frontiers in Molecular Neuroscience, Frontiers Media, 2018, 11, pp.321. ⟨10.3389/fnmol.2018.00321⟩
ISSN: 1662-5099
DOI: 10.3389/fnmol.2018.00321⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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