PFF induced striatal neurodegeneration model for preclinical proof of concept studies targeting alpha‐synuclein pathology

Abstract

AbstractBackgroundParkinson’s disease (PD) is the most common neurodegenerative movement disorder with more than half of the patients developing dementia about 10 years later, and is characterized by the accumulation of alpha‐synuclein protein aggregates in the PD brain. These inclusions, also called Lewy bodies, accompanied with the degeneration of dopaminergic neurons are the neuropathological hallmark of this devastating incurable disease. Currently a lot of effort is put in studying the involvement of different forms of alpha‐synuclein, i.e. monomeric, oligomeric, fibrillar and aggregated forms or different post translational modifications of the protein, and their contribution to disease progression. Targeting alpha‐synuclein might thus be of potential therapeutic value. Since the research field lacks good and consistent animal models for preclinical research, we’ve set up a mouse model based on the striatal administration of sonicated preformed fibrils (PFF).MethodIn brief, we performed unilateral stereotactical injections in the dorsal striatum of young wild type mice with sonicated PFF’s (n = 8/group). PFF injected mice were sacrificed after 5, 9 and 13 weeks, a control group of vehicle injected mice (n = 7) was sacrificed after 9 weeks. Phosphorylated alpha‐synuclein (pSer129) seed and spread and dopaminergic neurodegeneration was visualized by IHC in different brain regions both ipsilateral and contralateral.ResultPhosphorylated alpha‐synuclein (pSer129) positive inclusions were shown to be present in Striatum, substantia nigra (SN) and amygdala in the ipsilateral hemisphere already after 5 weeks, indicating clear spreading of pathology. Interestingly, in the contralateral hemisphere we were able to detect clear pSer129 alpha‐synuclein in the amygdala and striatum 5 and 9 weeks after injection respectively, demonstrating the progressive nature of this model. To assess whether the observed pathology also affected the dopaminergic circuitry we quantified the loss of synaptic tyrosine hydroxylase positive terminals in the striatum and found a significant decrease already 5 weeks after PFF administration.ConclusionThis alpha‐synuclein preformed fibril based model, which shows clear progressive seed and spread pathology and a clear decrease in dopaminergic nerve terminals in the striatum, can be of great importance to the research field to assess in vivo therapeutic interventions based on targeting alpha‐synuclein pathology.