In vitro models of synucleinopathies: informing on molecular mechanisms and protective strategies

Alpha-synuclein (α-Syn) is a central player in Parkinson's disease (PD) and in a spectrum of neurodegenerative diseases collectively known as synucleinopathies. The protein was first associated with PD just over 20 years ago, when it was found to (i) be a major component of Lewy bodies and (ii) to be also associated with familial forms of PD. The characterization of α-Syn pathology has been achieved through postmortem studies of human brains. However, the identification of toxic mechanisms associated with α-Syn was only achieved through the use of experimental models. In vitro models are highly accessible, enable relatively rapid studies, and have been extensively employed to address α-Syn-associated neurodegeneration. Given the diversity of models used and the outcomes of the studies, a cumulative and comprehensive perspective emerges as indispensable to pave the way for further investigations. Here, we subdivided in vitro models of α-Syn pathology into three major types: (i) models simulating α-Syn fibrillization and the formation of different aggregated structures in vitro, (ii) models based on the intracellular expression of α-Syn, reporting on pathogenic conditions and cellular dysfunctions induced, and (iii) models using extracellular treatment with α-Syn aggregated species, reporting on sites of interaction and their downstream consequences. In summary, we review the underlying molecular mechanisms discovered and categorize protective strategies, in order to pave the way for future studies and the identification of effective therapeutic strategies. This article is part of the Special Issue "Synuclein".