Send to

Choose Destination
Front Neurosci. 2018 Sep 4;12:621. doi: 10.3389/fnins.2018.00621. eCollection 2018.

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

Author information

Department of Translational Science and Molecular Medicine, Michigan State University, Grand Rapids, MI, United States.
Mercy Health Hauenstein Neuroscience Medical Center, Grand Rapids, MI, United States.


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.


Parkinson’s disease; alpha-synuclein; animal models; preformed fibrils; synucleinopathy

Supplemental Content

Full text links

Icon for Frontiers Media SA Icon for PubMed Central
Loading ...
Support Center