Review: Spreading the word: precise animal models and validated methods are vital when evaluating prion-like behaviour of alpha-synuclein

Synucleinopathies are characterized by abnormal proteinaceous aggregates, mainly composed of fibrillar -synuclein (-syn). It is now believed that -syn can form small aggregates in a restricted number of cells, that propagate to neighbouring cells and seed aggregation of endogenous -syn, in a prion-like manner'. This process could underlie the stereotypical progression of Lewy bodies described by Braak and colleagues across different stages of Parkinson's disease (PD). This prion-like behaviour of -syn has been recently investigated in animal models of PD or multiple system atrophy (MSA). These models investigate the cell-to-cell transfer of -syn seeds, or the induction and spreading of -syn pathology in transgenic or wild-type rodent brain. In this review, we first outline the involvement of -syn in Lewy body diseases and MSA, and discuss how prion-like' mechanisms can contribute to disease. Thereon, we debate the relevance of animal models used to study prion-like propagation. Finally, we review current main histological methods used to assess -syn pathology both in animal models and in human samples and their relevance to the disease. Specifically, we discuss using -syn phosphorylated at serine 129 as a marker of pathology, and the novel methods available that allow for more sensitive detection of early pathology, which has relevance for modelling synucleinopathies.