Abstract Body

Dopaminergic neuronal cell death, associated with intracellular α‐synuclein (α‐syn)-rich inclusions termed Lewy bodies, characterises Parkinson’s disease (PD). Using Lewy bodies extracted from PD brains, we characterized the synucleinopathy in non-human primates (NHPs), by comparing the effects of these large human aggregates with solutions of soluble and smaller α-syn aggregates. To our biggest surprise, while these small α-syn aggregates did not led to neuronal death in mice, NHPs showed neurodegeneration after small aggregates injection; to the same extent of big aggregates. Such aggregates differed by their size but also by their folding properties, suggesting that, within human brains, conformational strain diversity exists. In vitro, various α-syn fibril polymorphs have been obtained from distinct fibrillization conditions and were selected by amyloid monitoring using the probe Thioflavin T (ThT). We report that, concurrently with classical ThT-positive products, fibrillization in saline also gives rise to polymorphs that are invisible to ThT (τ^-), and that crowd the fibril preparations. The emergence of τ^- polymorphs has been ignored so far or mistaken for fibrillization inhibitions/failures. Compared to their ThT-positive counterparts, these new τ^- polymorphs present a yet undescribed atomic organization, an exacerbated propensity towards self-replication in cortical neurons and spreading of brain pathology in living mice. That the human brain aggregate diversity finds an in vitro counterpart where different polymorphs emerge in physiological conditions, strongly suggests that the search for therapeutic solutions must incorporate all adopted structures for hoping to have an impact upon disease progression.