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

Emerging findings suggest that Parkinson's disease (PD) pathology (alpha-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 alpha-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 alpha-synuclein were elevated in enteric and brain neurons in DSS-treated PD mice, suggesting that mild gut inflammation accelerates alpha-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 alpha-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.