BMI SEMINAR // Erwan Bezard - Primate-specific susceptibility to neurodegeneration and synucleinopathy induced by patient-derived a-synuclein extracts

Dopaminergic neuronal cell death, associated with intracellular α‐synuclein (α‐syn)-rich protein aggregates (termed ‘Lewy bodies’), is a well-established characteristic of Parkinson’s disease. Much evidence, accumulated from multiple experimental models has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. The presentation will contain two parts. In the first part, we have used an unbiased machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.

In the second part we test the hypothesis, in primates, that synucleinopathy spreads from the enteric nervous system to the central nervous system. Here we show 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 primate model. This suggests that the progression of α-synuclein pathology might be either caudo-rostral and rostro-caudal, varying between patients and disease subtypes.