The connectome is necessary but not sufficient for the spread of alpha-synuclein pathology in rats

Certain neuronal populations are selectively vulnerable to alpha -synuclein pathology in Parkinson’s Disease, yet the reasons for this selectivity are unclear. Pathology affects neuronal populations that are anatomically connected although the contribution of neuronal connectivity remains to be quantitatively explored. Herein, we simulate the contribution of the connectome alone to the spread of arbitrary aggregates using a computational model of temporal spread within an abstract representation of the mouse mesoscale connectome. Our simulations are compared with the neuron-to-neuron spread of alpha -synuclein that has been observed with in vivo spreading experiments in rats. We find that neuronal connectivity appears to be compatible with the spreading pattern of alpha -synuclein pathology however, it may be per se insufficient to determine the anatomical pattern of protein spreading observed in experimental animals, suggesting a role of selective vulnerability of neuronal pathways to alpha -synuclein diffusion, accumulation and pathology. Graphical abstract