Clinical and Pre-Clinical Evidence for Enteric α-Synuclein Involvement in Parkinson's Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease, presenting with the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and motor symptoms. Categorized as a synucleinopathy, the pathological hallmark of PD is intracellular filamentous Lewy bodies (LB), which are formed from protopathic aggregates. The most prevalent of these proteins is the presynaptic protein ɑ-synuclein (α-syn). While commonly attributed to neuronal death in SNpc, postmortem studies have shown α-syn immunoreactivity and LB pathology in the peripheral, central, and enteric nervous system (ENS). While the etiology of misfolded α-syn is unknown, various gut microbiota and substrates are associated with α-syn dysfunction. Gastrointestinal (GI) dysfunction, a common feature in the prodromal phase of PD patients, and histological evidence have led to the Braak hypothesis of misfolded α-syn commencement in the ENS and propagation to brainstem nuclei including the SNpc via the vagus nerve. Altered or stressed gut environment is thought to contribute to the misfolding of α-syn that subsequently initiates or spurs its propagation from the gut myenteric plexus. This review covers clinical and pre-clinical evidence of the involvement of enteric α-syn in PD related to GI dysfunction and brain pathology.