Gastrointestinal Immunity and Alpha-Synuclein

Abstract

The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive network, even in the most primitive organisms. Neuropeptides exhibit potent antimicrobial activity in the vicinity of the nerve and attract the innate and adaptive immune systems to help confine the invading agent. Alpha-synuclein (αS) has many biophysical characteristics of antimicrobial peptides and binds small vesicles such as those carrying endocytosed viruses. It is induced in nerve cells in response to viral and bacterial infections. It renders the nerve cell resistant to viral infection and propagation. It signals the immune system by attracting neutrophils and macrophages, and by activating dendritic cells. Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates. Overproduction of αS in the enteric nervous system (ENS) and its chronic trafficking to the CNS may damage nerves and lead to Parkinson's disease. Targeting the formation of αS aggregates in the ENS may therefore slow the progression of the disease.

Keywords: Antimicrobial peptides; Parkinson’s disease; alpha-synuclein; enteric nervous system.

Fig.1

Subepithelial enteric neurons visualized with PGP9.5 immunostaining from human small intestine. The epithelial layer was detached from the underlying lamina propria by EDTA treatment [51] and visualized as described [25].

Fig.2

Macrophages cluster around neurons expressing αS. Human duodenal biopsy from a pediatric patient presenting with upper GI distress. Left, immune-stained for αS; Right, immune-stained for CD68 antigen (macrophage) [25].

Fig.3

Cartoon illustration of the proposed immune roles of αS within the ENS.