Preformed Fibrils Generated From Mouse Alpha-Synuclein Produce More Inclusion Pathology In Rats Than Fibrils Generated From Rat Alpha-Synuclein

Background: Alpha-synuclein (alpha-syn) preformed fibril (PFF)-induced pathology can be used to study the features and progression of synucleinopathies, such as Parkinson's disease. Intrastriatal injection of mouse alpha-syn PFFs produce accumulation of alpha-syn pathology in both mice and rats. Previous studies in mice have revealed that greater sequence homology between the alpha-syn amino acid sequence used to produce PFFs with that of the endogenous host alpha-syn increases alpha-syn pathology in vivo.New methods: Based on the prediction that greater sequence homology will result in more alpha-syn pathology, PFFs generated from recombinant rat alpha-syn (rPFFs) were used instead of PFFs produced from recombinant mouse alpha-syn (mPFFs), which are normally used in the model. Rats received unilateral intrastriatal injections of either rPFFs or mPFFs and accumulation of alpha-syn phosphorylated at serine 129 (pSyn) was examined at 1-month post-surgery.Results: Rats injected with mPFFs exhibited abundant accumulation of alpha-syn inclusions in the substantia nigra and cortical regions, whereas in rats injected with rPFFs had significantly fewer SNpc neurons containing pSyn inclusions (approximate to 60% fewer) and little, if any, pSyn inclusions were observed in the cortex.Conclusions: Our results suggest that additional factors beyond the degree of sequence homology between host alpha-syn and injected recombinant alpha-syn impact efficiency of seeding and subsequent inclusion formation. More practically, these findings caution against the use of rPFFs in the rat preformed fibril model.