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

Abstract

Parkinson's disease (PD) is the second most common neu-rodegenerative disease, presenting with the loss of dopa-minergic neurons in the substantia nigra pars compacta (SNpc) and motor symptoms. Categorized as a synuclei-nopathy, the pathological hallmark of PD is intracellular fila-mentous Lewy bodies (LB), which are formed from protopa-thic 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 histolo-gical evidence have led to the Braak hypothesis of misfol-ded 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.