The Neural Gut-Brain Axis of Pathological Protein Aggregation in Parkinson's Disease and Its Counterpart in Peroral Prion Infections

Abstract

A neuropathological hallmark of Parkinson's disease (PD) is the cerebral deposition of abnormally aggregated α-synuclein (αSyn). PD-associated αSyn (αSyn^PD) aggregates are assumed to act, in a prion-like manner, as proteinaceous nuclei ("seeds") capable of self-templated propagation. Braak and colleagues put forward the idea of a neural gut-brain axis mediating the centripetal spread of αSyn^PD pathology from the enteric nervous system (ENS) to the brain in PD. This has sparked great interest and initiated passionate discussions both in support of and opposing the suggested hypothesis. A precedent for the spread of protein seeds or seeding from the gastro-intestinal (GI) tract to the central nervous system (CNS) had been previously revealed for pathological prion protein in peroral prion infections. This article scrutinizes the similarities and dissimilarities between the pathophysiological spread of disease-associated protein aggregation along the neural gut-brain axis in peroral prion infections and PD. On this basis, evidence supporting the proposed neural gut-brain axis in PD is concluded to be not as robust as that established for peroral prion infections. New tools for the ultrasensitive detection of αSyn^PD-associated seeding activity in archived or fresh human tissue samples such as real-time quaking induced conversion (RT-QuIC) or protein misfolding cyclic amplification (PMCA) assays can possibly help to address this deficit in the future.

Keywords: Parkinson’s disease; alpha-synuclein; enteric nervous system; peroral prion infections; prion protein; seeds; spread; vagus nerve.

Figure 1

Mechanistic model of nucleation-dependent protein aggregation thought to underly the self-assembly and propagation of pathological αSyn^PD, PrP^TSE or other proteinaceous seeds in PD, TSE and further neurodegenerative protein aggregation diseases, respectively. Under certain conditions, (usually monomeric) protein conformers can spontaneously, or driven by genetic factors, assemble into β-sheet-rich aggregates that constitute self-replicative protein particles, or seeds. Such initial seed formation, referred to as primary nucleation, is controlled by a high kinetic barrier. Primary nucleation is exemplarily depicted for hamster PrP, schematically showing the aggregation of PrP monomers (1, [7]) into a PrP^TSE seed (2, [8]). Once proteinaceous seeds have been endogenously formed, or exogenously entered the organism, they can swiftly recruit and attach further monomers of their constitutive proteins. In this process of elongation, new aggregate mass is generated by the attachment of monomeric species to the ends of the seeding-active particles. Additionally, secondary nucleation may occur by the formation of new nucleation sites on the particle surface. When protein particles with primary or secondary nucleation sites fragment into smaller aggregates, progeny seeds enter the replication cycle and further propagate the pathological protein state. The figure was produced, with modifications, following a previously published template [4] in consideration of Meisl et al. [9]. Credits for mounted image components: (1) https://www.rcsb.org/structure/4YXL (accessed on 16 July 2021): crystal structure of Syrian hamster prion protein complexed with POM1 FAB is licensed under the PDB Privacy and Usage Policy, and (2) https://www.biorxiv.org/content/10.1101/2021.02.14.431014v2 (accessed on 16 July 2021): structure of an infectious mammalian prion is licensed under the Creative Commons CC0 1.0 Universal (CC0 1.0) Public Domain Dedication.

Figure 2

Pictorial representation of the neural gut–brain axis thought to be involved in the centripetal spread of pathological protein aggregation from the intestine to the CNS in both peroral prion infections as well as PD. As established in great detail for perorally acquired TSE early spread of prions and PrP^TSE pathology to the CNS occurs from ENS ganglia in a retrograde direction along parasympathetic and sympathetic efferents of the vagus and splanchnic nerves, to the DMV in the medulla oblongata and the IML in the spinal cord, respectively (reviewed in: [46,48]). A similar concept was subsequently proposed for the propagation of LP in PD from enteric ganglia in the gastrointestinal tract to the CNS, initially with respect to parasympathetic and later also with respect to sympathetic spreading pathways [14,73,76]. Dashed blue and red arrows indicate retrograde spread via efferent parasympathetic or sympathetic projections of the vagus or splanchnic nerves, respectively, for both peroral prion infections and PD. Dashed grey arrows mark spinal ascension of PrP^TSE pathology or LP to the brain following invasion of the IML at thoracic spinal cord levels of splanchnic innervation [46,73]. The figure was produced, with modifications, following templates from McBride et al. [32] and Mabbott and MacPherson [48]. Credits for mounted image components: “Blausen 0838 Sympathetic Innervation” and “Blausen 0703 Parasympathetic Innervation” by Bruce Blaus are licensed under the Creative Commons Attribution 3.0 Unported License (CC BY 3.0); “Anatomic structure of enteric plexus” (image ID FK8KPF) is licensed by Alamy Limited (Abingdon, UK, invoice number IY01945617). AP, area postrema; CMG, celiac or mesenteric ganglion; DMV, dorsal motor nucleus of the vagus nerve; DRG, dorsal root ganglion; ENS, enteric nervous system; IML, intermediolateral cell column; L, border between thoracic and lumbar spinal cord; MO, medulla oblongata; NG, nodose ganglion; SN, splanchnic nerves; STN, solitary tract nucleus; T, border between cervical and thoracic spinal cord; VN, vagus nerve.