Bidirectional gut-to-brain and brain-to-gut propagation of synucleinopathy in non-human primates

Abstract

<jats:title>Abstract</jats:title> <jats:p>In Parkinson’s disease, synucleinopathy is hypothesized to spread from the enteric nervous system, via the vagus nerve, to the CNS. Here, we compare, in baboon monkeys, the pathological consequences of either intrastriatal or enteric injection of α-synuclein-containing Lewy body extracts from patients with Parkinson’s disease. This study shows that patient-derived α-synuclein aggregates are able to induce nigrostriatal lesions and enteric nervous system pathology after either enteric or striatal injection in a non-human primate model. This finding suggests that the progression of α-synuclein pathology might be either caudo-rostral or rostro-caudal, varying between patients and disease subtypes. In addition, we report that α-synuclein pathological lesions were not found in the vagal nerve in our experimental setting. This study does not support the hypothesis of a transmission of α-synuclein pathology through the vagus nerve and the dorsal motor nucleus of the vagus. Instead, our results suggest a possible systemic mechanism in which the general circulation would act as a route for long-distance bidirectional transmission of endogenous α-synuclein between the enteric and the central nervous systems. Taken together, our study provides invaluable primate data exploring the role of the gut-brain axis in the initiation and propagation of Parkinson’s disease pathology and should open the door to the development and testing of new therapeutic approaches aimed at interfering with the development of sporadic Parkinson’s disease.</jats:p>

The Logic and Pitfalls of Parkinson's Disease as “Brain‐First” Versus “Body‐First” Subtypes

“…[2][3][4][5][6] This "brain-first"/"body-first" division is supported primarily by animal models demonstrating bidirectional extension between the gut and the brain of alpha-synuclein pathology along sympathetic and parasympathetic pathways. 6,7 This most recent study by Horsager and colleagues suggests that some patients exhibit significantly more peripheral organ pathology at the time of initial assessment than others. Although the subtype hypothesis was not proposed as a panacea to explain all of the clinical and pathological variability of PD, there is need for a critical appraisal of its validity and utility in explaining the heterogeneity and individual complexity of PD and informing the direction of future research.…”

Microbiome or Infections: Amyloid-Containing Biofilms as a Trigger for Complex Human Diseases

“…However, studies by one group found that the pathology failed to progress past the dorsal motor nucleus (149,150). Another group injected baboons with patient-derived Lewy body extracts and found that pathology spread to the central nervous system through circulation rather than via the vagus nerve (151). Regardless, there is mounting evidence indicating that bacterial amyloids such as curli, present at high levels in biofilms in the gut, are capable of cross-seeding αSyn aggregation and that αSyn aggregates are capable of spreading from the gut to the brain as a possible initiating event in PD (112,127,134,139,(146)(147)(148)151).…”

Gut Microbiota Approach—A New Strategy to Treat Parkinson’s Disease

“…The levels of a-syn in the blood of baboons injected were increased, which was positively correlated with the levels of a-syn in ENS. Endogenous a-syn may be transmitted long-distance and bidirectional between ENS and the brain through the circulatory system (Arotcarena et al, 2020).…”