Induction of de novo ?-synuclein fibrillization in a neuronal model for Parkinson's disease.

ABSTRACT: Lewy bodies (LBs) are intraneuronal inclusions consisting primarily of fibrillized human ?-synuclein (h?-Syn) protein, which represent the major pathological hallmark of Parkinson's disease (PD). Although doubling h?-Syn expression provokes LB pathology in humans, h?-Syn overexpression does not trigger the formation of fibrillar LB-like inclusions in mice. We hypothesized that interactions between exogenous h?-Syn and endogenous mouse synuclein homologs could be attenuating h?-Syn fibrillization in mice, and therefore, we systematically assessed h?-Syn aggregation propensity in neurons derived from ?-Syn-KO, ?-Syn-KO, ?-Syn-KO, and triple-KO mice lacking expression of all three synuclein homologs. Herein, we show that h?-Syn forms hyperphosphorylated (at S129) and ubiquitin-positive LB-like inclusions in primary neurons of ?-Syn-KO, ?-Syn-KO, and triple-KO mice, as well as in transgenic ?-Syn-KO mouse brains in vivo. Importantly, correlative light and electron microscopy, immunogold labeling, and thioflavin-S binding established their fibrillar ultrastructure, and fluorescence recovery after photobleaching/photoconversion experiments showed that these inclusions grow in size and incorporate soluble proteins. We further investigated whether the presence of homologous ?-Syn species would interfere with the seeding and spreading of ?-Syn pathology. Our results are in line with increasing evidence demonstrating that the spreading of ?-Syn pathology is most prominent when the injected preformed fibrils and host-expressed ?-Syn monomers are from the same species. These findings provide insights that will help advance the development of neuronal and in vivo models for understanding mechanisms underlying h?-Syn intraneuronal fibrillization and its contribution to PD pathogenesis, and for screening pharmacologic and genetic modulators of ?-Syn fibrillization in neurons.

SUBMITTER: Fares MB 

PROVIDER: S-EPMC4763739 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature