Modeling α-Synucleinopathy in Organotypic Brain Slice Culture with Preformed α-Synuclein Amyloid Fibrils

Autor: Katelyn Becker, Jiyan Ma, Amandine Roux, Xinhe Wang
Rok vydání: 2020
Předmět:
Research Report
0301 basic medicine
Synucleinopathies
animal diseases
pre-formed recombinant α-syn amyloid fibrils (PFFs)
environment and public health
Rats
Sprague-Dawley
Mice
chemistry.chemical_compound
0302 clinical medicine
Pregnancy
Cerebellum
neurotoxicity
heterocyclic compounds
Phosphorylation
Mice
Knockout
biology
Chemistry
Neurodegeneration
aggregation
Recombinant Proteins
Frontal Lobe
Cell biology
Female
synucleinopathy
Amyloid
organotypic brain slice culture
Mice
Transgenic
Models
Biological
Alpha-synuclein
03 medical and health sciences
Cellular and Molecular Neuroscience
Slice preparation
In vivo
medicine
Animals
Humans
Neurotoxicity
medicine.disease
Rats
nervous system diseases
Mice
Inbred C57BL
030104 developmental biology
nervous system
Synaptophysin
biology.protein
Neurology (clinical)
030217 neurology & neurosurgery
Ex vivo
Zdroj: Journal of Parkinson's Disease
ISSN: 1877-718X
1877-7171
Popis: Background: Synucleinopathy is a group of neurodegenerative disorders characterized by neurodegeneration and accumulation of alpha-synuclein (α-syn) aggregates in various brain regions. The detailed mechanism of α-syn-caused neurotoxicity remains obscure, which is partly due to the lack of a suitable model that retains the in vivo three-dimensional cellular network and allows a convenient dissection of the neurotoxic pathways. Recent studies revealed that the pre-formed recombinant α-syn amyloid fibrils (PFFs) induce a robust accumulation of pathogenic α-syn species in cultured cells and animals. Objective: Our goal is to determine whether PFFs are able to induce the pathogenic α-syn accumulation and neurotoxicity in organotypic brain slice culture, an ex vivo system that retains the in vivo three-dimensional cell-cell connections. Methods/Results: Adding PFFs to cultured wild-type rat or mouse brain slices induced a time-dependent accumulation of pathogenic α-syn species, which was indicated by α-syn phosphorylated at serine 129 (pα-syn). The PFF-induced pα-syn was abolished in brain slices prepared from α-syn null mice, suggesting that the pα-syn is from the phosphorylation of endogenous α-syn. Human PFFs also induced pα-syn in brain slices prepared from mice expressing human α-syn on a mouse α-syn-null background. Furthermore, the synaptophysin immunoreactivity was inversely associated with pα-syn accumulation and an increase of neuronal loss was detected. Conclusion: PFF-treatment of brain slices is able to induce key pathological features of synucleinopathy: pα-syn accumulation and neurotoxicity. This model will be useful for investigating the neurotoxic mechanism and evaluating efficacy of therapeutic approaches.
Databáze: OpenAIRE
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