Abstract
A neuropathological hallmark of Parkinson’s disease (PD) is the cerebral deposition of abnormally aggregated α-synuclein (αSyn). PD-associated αSyn (αSynPD) 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 αSynPD 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 αSynPD-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.
Highlights
The deposition of misfolded and aggregated alpha-synuclein in cerebral neuronal cell bodies or processes and associated with synapses [2] is a neuropathological hallmark of idiopathic Parkinson’s disease
That the vagus nerve can harbour PrPTSE had already previously been found in hamsters intraperitoneally challenged with scrapie [45]. While these findings indicated the vagus nerve as a conduit for prion infectivity or PrPTSE, taken in themselves, they did not provide information on the direction of spread
The hypothesis of a neural gut–brain axis mediating stereotypical spread of pathological prion-like protein aggregation in Parkinson’s disease, which originated from the work of Braak and colleagues as referenced above, has undergone a remarkable development in the past few years and triggered an ongoing multifaceted and controversial discussion [27,28,29,74,96,103]
Summary
The deposition of misfolded and aggregated alpha-synuclein (αSyn) in cerebral neuronal cell bodies or processes (referred to as Lewy bodies [LB] or Lewy neurites [LN], respectively [1]) and associated with synapses [2] is a neuropathological hallmark of idiopathic Parkinson’s disease (abbreviated in the following as PD, since other forms of Parkinson’s disease will not be addressed in this review). In one of the few papers that include original literature on the gut–brain axis in peroral prion infections in somewhat more detail, the authors state “An important research goal is to elucidate the degree of similarity between pathophysiological processes in PD and those of true prion disease” [29] In line with this approach, this article intends to provide a review of neural pathways along the gut–brain axis thought to mediate centripetal spread of PrPTSE and αSynPD seeds or seeding from the alimentary tract to the CNS. This review does not include findings on pathological αSyn species from non-PD αSyn aggregation diseases (e.g., dementia with Lewy bodies [DLB] or multiple system atrophy [MSA]), or on in vitro generated fibrillar or non-fibrillar αSyn assemblies, because such αSyn species may not necessarily share the pathophysiological properties of αSynPD with respect to the hypothetized gut–brain axis in PD
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