Quality Over Quantity: Advantages of Using Alpha-Synuclein Preformed Fibril Triggered Synucleinopathy to Model Idiopathic Parkinson's Disease.

Animal models have significantly advanced our understanding of Parkinson's disease (PD). Alpha-synuclein (alpha-syn) has taken center stage due to its genetic connection to familial PD and localization to Lewy bodies, one pathological hallmark of PD. Animal models developed on the premise of elevated alpha-synuclein via germline manipulation or viral vector-mediated overexpression are used to investigate PD pathophysiology and vet novel therapeutics. While these models represented a step forward compared to their neurotoxicant model predecessors, they rely on overexpression of supraphysiological levels of alpha-syn to trigger toxicity. However, whereas SNCA-linked familial PD is associated with elevated alpha-syn, elevated alpha-syn is not associated with idiopathic PD. Therefore, the defining feature of the alpha-syn overexpression models may fail to appropriately model idiopathic PD. In the last several years a new model has been developed in which alpha-syn preformed fibrils are injected intrastriatally and trigger normal endogenous levels of alpha-syn to misfold and accumulate into Lewy body-like inclusions. Following a defined period of inclusion accumulation, distinct phases of neuroinflammation and progressive degeneration can be detected in the nigrostriatal system. In this perspective, we highlight the fact that levels of alpha-syn achieved in overexpression models generally exceed those observed in idiopathic and even SNCA multiplication-linked PD. This raises the possibility that supraphysiological alpha-syn expression may drive pathophysiological mechanisms not relevant to idiopathic PD. We argue in this perspective that synucleinopathy triggered to form within the context of normal alpha-syn expression represents a more faithful animal model of idiopathic PD when examining the role of neuroinflammation or the relationship between alpha-syn aggregation and toxicity.