Ascendance of Abnormal α-synuclein Fibrils Through the Vagal Nerve in Parkinson's Disease

Abstract

Parkinson's disease (PD) is caused by the abnormal accumulation of α-synuclein fibrils (Lewy bodies) in the substantia nigra. The α-synuclein fibrils behave like prions. Autopsy shows that α-synucleinopathy ascends from the brain stem to the substantia nigra. In patients with PD, the α-synuclein pathology is frequently observed in the intestinal neural plexus. In animal models, injection of α-synuclein fibrils in the gastric wall or the peritoneum caused immunostaining for aggregated α-synuclein fibrils in the substantia nigra. In Finland and Sweden, truncal vagotomy, but not partial vagotomy, reduced the chance of developing PD to 50% in 35 years. Of note, not all patients with PD show ascending α-synuclein pathology in the brain and that truncal vagotomy reduced the chance of developing PD to half. Thus, α-synucleinopathy is likely to start from the intestinal neural plexus and ascends through the vagal nerve to the substantia nigra in at least 50% of patients with PD. Additionally, short-chain fatty acids (SCFA)-producing intestinal bacteria are reduced in PD. Although the underlying mechanisms are currently under investigation, the vagal nerve also senses SCFA and transmits signals to the central nervous system. This pathway is likely to be compromised by gut dysbiosis in PD.