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

A neuropathological hallmark of Parkinson's disease (PD) is the cerebral deposition of abnormally aggregated alpha-synuclein (alpha Syn). PD-associated alpha Syn (alpha Syn(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 alpha Syn(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 alpha Syn(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.