Modeling Parkinson's Disease With the Alpha-Synuclein Protein

Alpha-synuclein (alpha-Syn) is a key protein involved in Parkinson's disease (PD) pathology. PD is characterized by the loss of dopaminergic neuronal cells in the substantia nigra pars compacta and the abnormal accumulation and aggregation of alpha-Syn in the form of Lewy bodies and Lewy neurites. More precisely, the aggregation of alpha-Syn is associated with the dysfunctionality and degeneration of neurons in PD. Moreover, mutations in the SNCA gene, which encodes alpha-Syn, cause familial forms of PD and are the basis of sporadic PD risk. Given the role of the alpha-Syn protein in the pathology of PD, animal models that reflect the dopaminergic neuronal loss and the widespread and progressive formation of alpha-Syn aggregates in different areas of the brain constitute a valuable tool. Indeed, animal models of PD are important for understanding the molecular mechanisms of the disease and might contribute to the development and validation of new therapies. In the absence of animal models that faithfully reproduce human PD, in recent years, numerous animal models of PD based on alpha-Syn have been generated. In this review, we summarize the main features of the alpha-Syn pre-formed fibrils (PFFs) model and recombinant adeno-associated virus vector (rAAV) mediated alpha-Syn overexpression models, providing a detailed comparative analysis of both models. Here, we discuss how each model has contributed to our understanding of PD pathology and the advantages and weakness of each of them. Significance Here, we show that injection of alpha-Syn PFFs and overexpression of alpha-Syn mediated by rAAV lead to a different pattern of PD pathology in rodents. First, alpha-Syn PFFs models trigger the Lewy body-like inclusions formation in brain regions directly interconnected with the injection site, suggesting that there is an inter-neuronal transmission of the alpha-Syn pathology. In contrast, rAAV-mediated alpha-Syn overexpression in the brain limits the alpha-Syn aggregates within the transduced neurons. Second, phosphorylated alpha-Syn inclusions obtained with rAAV are predominantly nuclear with a punctate appearance that becomes diffuse along the neuronal fibers, whereas alpha-Syn PFFs models lead to the formation of cytoplasmic aggregates of phosphorylated alpha-Syn reminiscent of Lewy bodies and Lewy neurites.