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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Acknowledgments
We thank Iolanda Moreira for assistance in managing the animal colonies. We thank Dr. Flaviano Giorgini for critically reading the manuscript.
Funding
This work was funded by Fundação para a Ciência e Tecnologia, Portugal (PTDC/SAU-ORG/114083/2009). TFP was “Investigador FCT”; JEC is a postdoctoral FCT fellow (BPD/87647/2012); LVL is an “Investigador FCT”; TFO is supported by the DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB).
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12017_2016_8435_MOESM1_ESM.tif
Supplementary Figure 1. (A) α-Syn expression levels in the spinal cord of heterozygous (+/-) and homozygous (+/+) mice for the α-SynA53T transgene at the end of the experiment. Total tissue lysates were analyzed by Western blots stained for α-Syn and β-actin as loading control (TIFF 10419 kb)
12017_2016_8435_MOESM2_ESM.tif
Supplementary Figure 2. (A) Mortality and motor phenotype in mice overexpressing α-SynA53T in homozygosity and wt IL-1R gene (black bars) or no wt IL-1R gene (gray bars). (B) Expression of TNF-α and Sirt2 mRNA levels in the brains of transgenic mice with or without wt IL-1R gene (TIFF 84803 kb)
12017_2016_8435_MOESM3_ESM.tif
Supplementary Figure 3. Sirt1 mRNA expression levels in the brain of heterozygous (+/-) and homozygous (+/+) transgenic mice at the end of the experiment (TIFF 5185 kb)
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Guerreiro, P.S., Coelho, J.E., Sousa-Lima, I. et al. Mutant A53T α-Synuclein Improves Rotarod Performance Before Motor Deficits and Affects Metabolic Pathways. Neuromol Med 19, 113–121 (2017). https://doi.org/10.1007/s12017-016-8435-5
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DOI: https://doi.org/10.1007/s12017-016-8435-5