Alpha-synuclein and tau are abundantly expressed in the ENS of the human appendix and monkey cecum.

α-Synuclein (α-syn) proteinopathy in the neurons of the Enteric Nervous System (ENS) is proposed to have a critical role in Parkinson's disease (PD) onset and progression. Interestingly, the ENS of the human appendix harbors abundant α-syn and appendectomy has been linked to a decreased risk and delayed onset of PD, suggesting that the appendix may influence PD pathology. Common marmosets and rhesus macaques lack a distinct appendix (a narrow closed-end appendage with a distinct change in diameter at the junction with the cecum), yet the cecal microanatomy of these monkeys is similar to the human appendix. Sections of human appendix (n = 3) and ceca from common marmosets (n = 4) and rhesus macaques (n = 3) were evaluated to shed light on the microanatomy and the expression of PD-related proteins. Analysis confirmed that the human appendix and marmoset and rhesus ceca present thick walls comprised of serosa, muscularis externa, submucosa, and mucosa plus abundant lymphoid tissue. Across all three species, the myenteric plexus of the ENS was located within the muscularis externa with nerve fibers innervating all layers of the appendix/ceca. Expression of α-syn and tau in the appendix/cecum was present within myenteric ganglia and along nerve fibers of the muscularis externa and mucosa in all species. In the myenteric ganglia α-syn, p-α-syn, tau and p-tau immunoreactivities (ir) were not significantly different across species. The percent area above threshold of α-syn-ir and tau-ir in the nerve fibers of the muscularis externa and mucosa were greater in the human appendix than in the NHP ceca (α-syn-ir p<0.05; tau-ir p<0.05). Overall, this study provides critical translational evidence that the common marmoset and rhesus macaque ceca are remarkably similar to the human appendix and, thus, that these NHP species are suitable for studying the development of PD linked to α-syn and tau pathological changes in the ENS.

Acute Exposure to the Food-Borne Pathogen Listeria monocytogenes Does Not Induce α-Synuclein Pathology in the Colonic ENS of Nonhuman Primates.

INTRODUCTION: Gastrointestinal (GI) inflammation elicited by environmental factors is proposed to trigger Parkinson's disease (PD) by stimulating accumulation of pathological α-synuclein (α-syn) in the enteric nervous system (ENS), which then propagates to the central nervous system via the vagus nerve. The goal of this study was to model, in nonhuman primates, an acute exposure to a common food-borne pathogen in order to assess whether the related acute GI inflammation could initiate persistent α-syn pathology in the ENS, ultimately leading to PD. METHODS: Adult female cynomolgus macaques were inoculated by oral gavage with 1×108 colony-forming units (CFUs) Listeria monocytogenes (LM, n=10) or vehicle (mock, n=3) and euthanized 2 weeks later. Evaluations included clinical monitoring, blood and fecal shedding of LM, and postmortem pathological analysis of colonic and cecal tissues. RESULTS: LM inoculation of healthy adult cynomolgus macaques induced minimal to mild clinical signs of infection; LM shedding in feces was not seen in any of the animals nor was bacteremia detected. Colitis varied from none to moderate in LM-treated subjects and none to minimal in mock-treated subjects. Expression of inflammatory markers (HLA-DR, CD3, CD20), oxidative stress (8-OHDG), α-syn, and phosphorylated-α-syn in the enteric ganglia was not significantly different between treatment groups. DISCUSSION: Our results demonstrate that cynomolgus macaques orally inoculated with LM present with a clinical response that resembles human LM exposure. They also suggest that acute exposure to food-borne pathogens is not sufficient to induce significant and persistent α-syn changes in healthy adult female subjects. Based on the results of this limited experimental setting, we propose that, if LM has a role in PD pathology, other underlying factors or conditions, such as male sex, inflammatory bowel disease, exposure to toxins, dysbiosis, and/or aging, are needed to be present.