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.

Automated summary

The study shows that using rPFFs instead of mPFFs in rats results in significantly less alpha-syn pathology, indicating that factors other than sequence homology affect seeding efficiency and inclusion formation. Additionally, caution is advised against using rPFFs in the rat preformed fibril model.