DOI: 10.1007/s12017-016-8435-5 Pages: 113-121
Article Type: Original Paper

Mutant A53T α-Synuclein Improves Rotarod Performance Before Motor Deficits and Affects Metabolic Pathways

1. Universidade de Lisboa, Faculdade de Medicina, Instituto de Medicina Molecular

2. Universidade Nova de Lisboa, Centro de Estudos de Doenças Crónicas, CEDOC, NOVA Medical School

3. APDP – Associação Protectora dos Diabéticos de Portugal

4. University Medical Center Göttingen, Department of Neurodegeneration and Restorative Research, Center for Nanoscale Microscopy and Molecular Physiology of the Brain

5. Instituto Gulbenkian de Ciência

6. Flanders Institute for Biotechnology (VIB), VIB Switch Laboratory

7. KU Leuven, Switch Laboratory, Department of Cellular and Molecular Medicine

Correspondence to:
Teresa F. Pais
Tel: +351 21 4407958
Email: tfariapais@gmail.com

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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.

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  • Accepted: Aug 10, 2016
  • Online: Aug 17, 2016

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