Abstract
Animal models have significantly advanced our understanding of Parkinson’s disease (PD). Alpha-synuclein (α-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 α-syn to trigger toxicity. However, whereas SNCA-linked familial PD is associated with elevated α-syn, elevated α-syn is not associated with idiopathic PD. Therefore, the defining feature of the α-syn overexpression models may fail to appropriately model idiopathic PD. In the last several years a new model has been developed in which α-syn preformed fibrils are injected intrastriatally and trigger normal endogenous levels of α-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 α-syn achieved in overexpression models generally exceed those observed in idiopathic and even SNCA multiplication-linked PD. This raises the possibility that supraphysiological α-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 α-syn expression represents a more faithful animal model of idiopathic PD when examining the role of neuroinflammation or the relationship between a-syn aggregation and toxicity.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 7–10 million individuals worldwide
We offer that that α-syn preformed fibrils of α-syn (PFFs) model may be better suited for studies of neuroinflammation and the relationship between α-syn aggregation and toxicity in idiopathic PD
The ability to advance our understanding of pathophysiology in idiopathic PD and predict the efficacy of novel therapeutics is dependent on the fidelity of animal models to the disease state
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 7–10 million individuals worldwide. Development of Abundant Lewy-Like Pathology in Multiple Extra Nigrostriatal Regions The α-syn PFF model has since been extended to wildtype mice (Luk et al, 2012a) and rats (Paumier et al, 2015; Abdelmotilib et al, 2017; Duffy et al, 2018) and most recently non-human primates (Shimozawa et al, 2017) These studies demonstrate that direct intracerebral injection of α-syn PFFs leads to accumulation of insoluble pSyn inclusions resembling Lewy pathology, all taking place in an environment of normal endogenous α-syn expression levels. As rat and mouse α-syn differs from human α-syn by eight amino acids, it is plausible that overexpression of the foreign human protein may initiate an artificial inflammatory response
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