Early alpha-synuclein accumulation, oxidative stress and inflammation in the proximal colon of c-rel-/- mouse model of Parkinson's disease

A growing body of evidence links the gastrointestinal tract to Parkinson's disease (PD) development. The research by Braak and colleagues, based on analyzing post-mortem samples from PD patients, suggests that the pathology begins in the gut and progresses to the brain. Our recent work shows that PD brains and PD PBMCs display reduced DNA-binding activity of the NF-κB/c-Rel subunit, a neuroprotective transcription factor that promotes brain expression of mitochondrial regulators such as B-cell lymphoma-extra-large (Bcl-xL), uncoupling protein 4 (UCP4), and manganese superoxide dismutase (MnSOD). Previous studies have also shown that male mice lacking the NF-κB/c-Rel subunit (c-rel-/- mice) develop age-related parkinsonian neuropathology linked to both non-motor and motor symptoms. They exhibit a Braak pattern of α-synuclein (α-syn) deposition, beginning with early gut involvement marked by constipation and α-syn accumulation in the distal colon from 2 months old. Here, we further examine the progression of intestinal pathology in the proximal colon of c-rel-/- male mice which is connected to the brain via the vagus nerve, using microscopy, biochemistry, and multispectral optoacoustic tomography. At 2 months, α-syn and phosphorylated α-syn accumulation was detected in the myenteric plexus of c-rel-/- mice, with significantly greater accumulation at 10 months. Intestinal synucleinopathy was accompanied by notable oxidative stress, evidenced by increased NADPH oxidase activity and higher levels of 3-nitrotyrosine-modified proteins in the proximal colon. By 10 months, c-rel-/- mice showed gut inflammation with elevated interleukin-6 expression, infiltration of CD11b + Ly6G+ neutrophils, and increased oxygenated hemoglobin in the proximal colon, along with colon shortening and loss of TH-positive neurons. These findings, in addition to supporting the role of NF-κB/c-Rel dysregulation in PD pathophysiology, show that c-rel-/- mice develop progressive PD-like pathology in the proximal colon and provide an invaluable model for studying the potential gut-to-brain spread of endogenous α-syn via the vagus.