Injection of α-syn-98 Aggregates Into the Brain Triggers α-Synuclein Pathology and an Inflammatory Response.

Pathological aggregation of alpha-synuclein alpha-syn) is a major component of Lewy bodies (LB), which play a central role in pathogenesis of Parkinson's disease (PD). Differential expression of alpha-syn isoforms has been shown in PD. Isoform alpha-syn-98 is generated by excision of exon-3 and exon-5 of the alpha-syn gene. In contrast to the canonical full-length alpha-syn isoform (alpha-syn140), little is known about the function of the alpha-syn-98 isoform. In the present study, to identify the potential role of alpha-syn-98 protein in PD, we examined the effects of exogenous recombinant insoluble alpha-syn-98 aggregates on alpha-syn pathology and inflammatory responses in the midbrain. After injection of alpha-syn-98 aggregates into the substantia nigra (SN), mice exhibited motor dysfunction accompanied by nigral dopaminergic neuron loss. In addition, alpha-syn-98 aggregates injection resulted in a significant increase in phosphorylation of endogenous alpha-syn. Accumulations of alpha-syn were co-localized with p62 and ubiquitin, which suggests alpha-syn-98 aggregates-induced pathology exhibits properties similar to human LB. Many glial cells were activated after alpha-syn-98 aggregates injection. In addition, expression of NF-kappa B, interleukin 6 (IL6), and tumor necrosis factor-alpha (TNF-alpha) and levels of oxidative stress increased after alpha-syn-98 aggregates injection. Our results suggest that alpha-syn-98 may play a crucial role in the pathogenesis of PD.