title: Mutant A53T α-Synuclein Improves Rotarod Performance Before Motor Deficits and Affects Metabolic Pathways.
abstract: The protein α-synuclein (α-Syn) interferes with glucose and lipid uptake and also activates innate immune cells. However, it remains unclear whether α-Syn or its familial mutant forms contribute to metabolic alterations and inflammation in synucleinopathies, such as Parkinson's disease (PD). Here, we address this issue in transgenic mice for the mutant A53T human α-Syn (α-SynA53T), a mouse model of synucleinopathies. At 9.5 months of age, mice overexpressing α-SynA53T (homozygous) had a significant reduction in weight, exhibited improved locomotion and did not show major motor deficits compared with control transgenic mice (heterozygous). At 17 months of age, α-SynA53T overexpression promoted general reduction in grip strength and deficient hindlimb reflex and resulted in severe disease and mortality in 50 % of the mice. Analysis of serum metabolites further revealed decreased levels of cholesterol, triglycerides and non-esterified fatty acids (NEFA) in α-SynA53T-overexpressing mice. In fed conditions, these mice also showed a significant decrease in serum insulin without alterations in blood glucose. In addition, assessment of inflammatory gene expression in the brain showed a significant increase in TNF-α mRNA but not of IL-1β induced by α-SynA53T overexpression. Interestingly, the brain mRNA levels of Sirtuin 2 (Sirt2), a deacetylase involved in both metabolic and inflammatory pathways, were significantly reduced. Our findings highlight the relevance of the mechanisms underlying initial weight loss and hyperactivity as early markers of synucleinopathies. Moreover, we found that changes in blood metabolites and decreased brain Sirt2 gene expression are associated with motor deficits.
authors.affiliation: Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal.|VIB Switch Laboratory, Flanders Institute for Biotechnology (VIB), Leuven, 3000, Belgium.|Switch Laboratory, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Patrícia S
authors.initials: PS
authors.lastname: Guerreiro
authors.affiliation: Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal.
authors.forename: Joana E
authors.initials: JE
authors.lastname: Coelho
authors.affiliation: Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.
authors.forename: Inês
authors.initials: I
authors.lastname: Sousa-Lima
authors.affiliation: Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.|APDP - Associação Protectora dos Diabéticos de Portugal, Rua Rodrigo da Fonseca, 1, 1250-189, Lisbon, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Macedo
authors.affiliation: Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal.
authors.forename: Luísa V
authors.initials: LV
authors.lastname: Lopes
authors.affiliation: Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School, Universidade Nova de Lisboa, Campo dos Mártires da Pátria, 130, 1169-056, Lisbon, Portugal.|Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain, University Medical Center Göttingen, 37073, Göttingen, Germany.
authors.forename: Tiago F
authors.initials: TF
authors.lastname: Outeiro
authors.affiliation: Faculdade de Medicina, Instituto de Medicina Molecular, Universidade de Lisboa, Av. Prof. Egas Moniz, 1649-028, Lisbon, Portugal. tfariapais@gmail.com.|Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6, 2780-156, Oeiras, Portugal. tfariapais@gmail.com.
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Pais
mesh_terms: D000367:Age Factors; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight / Q000235:genetics; D001923:Brain Chemistry / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D018737:Hand Strength; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D020734:Parkinsonian Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D017354:Point Mutation; D012021:Reflex, Abnormal / Q000235:genetics; D045442:Rotarod Performance Test; D056565:Sirtuin 2 / Q000096:biosynthesis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D051844:alpha-Synuclein / Q000235:genetics* / Q000502:physiology
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D009419:Nerve Tissue Proteins; D014409:Tumor Necrosis Factor-alpha; D051844:alpha-Synuclein; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2
keywords: Lipid metabolism; Sirtuins; Synucleinopathies