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

Abstract

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

Evidence for bidirectional and trans-synaptic parasympathetic and sympathetic propagation of alpha-synuclein in rats

“…Since it has been reported that the LC projects mainly to the SNr [6, 55], it seems plausible that the additional asyn pathology of the SNr was caused by asyn propagation through LC connections. Though neuronal connectivity is necessary, additional factors might contribute to the anatomical pattern of asyn pathology propagation [32]. Overall, our findings suggest that seeded BAC rats show asyn propagation through Braak stages 1, 2, and 3 [9, 10].…”

Brain iron enrichment attenuates α‐synuclein spreading after injection of preformed fibrils

“…Strikingly, not all anatomical connections were involved in α‐syn spreading pathology and the ones affected displayed unequal amounts of pS129‐α‐syn signal. It was suggested that the number of neuronal projections between regions and the projection length could influence the vulnerability of regions, presuming that anatomical connectivity is an influencing factor but does not exclusively determine the spreading pathology of α‐syn (Oliveira et al 2019).…”