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Chronic Mild Gut Inflammation Accelerates Brain Neuropathology and Motor Dysfunction in α-Synuclein Mutant Mice

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Abstract

Emerging findings suggest that Parkinson’s disease (PD) pathology (α-synuclein accumulation) and neuronal dysfunction may occur first in peripheral neurons of the autonomic nervous system including the enteric branches of the vagus nerve. The risk of PD increases greatly in people over the age of 65, a period of life in which chronic inflammation is common in many organ systems including the gut. Here we report that chronic mild focal intestinal inflammation accelerates the age of disease onset in α-synuclein mutant PD mice. Wild-type and PD mice treated with 0.5% dextran sodium sulfate (DSS) in their drinking water for 12 weeks beginning at 3 months of age exhibited histological and biochemical features of mild gut inflammation. The age of onset of motor dysfunction, evaluated using a rotarod test, gait analysis, and grip strength measurements, was significantly earlier in DSS-treated PD mice compared to control PD mice. Levels of the dopaminergic neuron marker tyrosine hydroxylase in the striatum and numbers of dopaminergic neurons in the substantia nigra were reduced in PD mice with gut inflammation. Levels of total and phosphorylated α-synuclein were elevated in enteric and brain neurons in DSS-treated PD mice, suggesting that mild gut inflammation accelerates α-synuclein pathology. Markers of inflammation in the colon and brain, but not in the blood, were elevated in DSS-treated PD mice, consistent with retrograde transneuronal propagation of α-synuclein pathology and neuroinflammation from the gut to the brain. Our findings suggest that interventions that reduce gut inflammation may prove beneficial in the prevention and treatment of PD.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

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Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, 21224, USA

    Yuki Kishimoto & Mark P. Mattson

  2. Immune Cells and Inflammation Section, National Institute on Aging Intramural Research Program, Baltimore, MD, 21224, USA

    Wandi Zhu & Jyoti M. Sen

  3. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21201, USA

    Waki Hosoda

  4. Immunology Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, 21105, USA

    Jyoti M. Sen

  5. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21201, USA

    Mark P. Mattson

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  1. Yuki Kishimoto
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Kishimoto, Y., Zhu, W., Hosoda, W. et al. Chronic Mild Gut Inflammation Accelerates Brain Neuropathology and Motor Dysfunction in α-Synuclein Mutant Mice. Neuromol Med 21, 239–249 (2019). https://doi.org/10.1007/s12017-019-08539-5

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