Toxicity of extracellular alpha-synuclein is independent of intracellular alpha-synuclein

Abstract

Parkinson′s disease (PD) pathology progresses throughout the nervous system affecting numerous neuronal structures. It has been postulated that the progression of the pathology is based on a prion-like disease mechanism partly due to the seeding effect of endocytosed alpha-synuclein (ASYN) on endogenous ASYN. The appearance of the pathology in dopaminergic neurons leads to neuronal cell death and motor symptoms. However, the effect on other neuronal structures is more inconsistent, leading to a higher variability in the prevalence of non-motor symptoms. Thus, the sensitivity to the pathology seems to vary among neuronal subtypes. Here, we analyzed the role of endogenous ASYN in the progression of PD-like pathology and the effect of monomeric and oligomeric ASYN as well as paraquat and rotenone on primary enteric, dopaminergic and cortical neurons from wild-type mice. Our results showed that pathology progression did not occur in the absence of endogenous ASYN and that dopaminergic neurons were more sensitive to ASYN and rotenone when compared to all other neuronal subtypes. Remarkably, the toxic effect of endocytosed ASYN-oligomers was independent of the presence of endogenous ASYN and directly related to the disturbance of the mitochondrial membrane potential. Thus, we suggest that the interaction between ASYN and mitochondria plays an important role in the toxicity of trans-synaptically transported ASYN and in the progression of PD pathology. These results question the prion-disease hypothesis and propose that endocytosed ASYN impairs the host′s mitochondrial function thereby also contributing to PD-pathology progression.

PrP meets alpha‐synuclein: Molecular mechanisms and implications for disease

“…Once internalized by recipient cells, aSyn aggregates may induce the misfolding and aggregation of intracellular aSyn, thus perpetuating the cycle of aggregate formation (Masuda-Suzukake et al, 2013;Paumier et al, 2015). Experiments using aSyn KO mice showed that endogenous aSyn is essential for the spreading of pathology, a process that does not require aSyn toxicity (Dening et al, 2022). Consequently, transmitting aSyn aggregates between cells may contribute to the progression of neurodegeneration observed in PD and related disorders.…”