Phosphorylation of endogenous \u03b1-synuclein induced by extracellular seeds initiates at the pre-synaptic region and spreads to the cell body

Shiori Awa,Takashi Nonaka,Masami Masuda-Suzukake,Genjiro Suzuki,Minoru Saito,Masato Hasegawa

doi:10.1038/s41598-022-04780-4

Abstract

Accumulation of phosphorylated α-synuclein aggregates has been implicated in several diseases, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), and is thought to spread in a prion-like manner. Elucidating the mechanisms of prion-like transmission of α-synuclein is important for the development of therapies for these diseases, but little is known about the details. Here, we injected α-synuclein fibrils into the brains of wild-type mice and examined the early phase of the induction of phosphorylated α-synuclein accumulation. We found that phosphorylated α-synuclein appeared within a few days after the intracerebral injection. It was observed initially in presynaptic regions and subsequently extended its localization to axons and cell bodies. These results suggest that extracellular α-synuclein fibrils are taken up into the presynaptic region and seed-dependently convert the endogenous normal α-synuclein that is abundant there to an abnormal phosphorylated form, which is then transported through the axon to the cell body.

Highlights

Accumulation of phosphorylated α-synuclein aggregates has been implicated in several diseases, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and is thought to spread in a prion-like manner
In PD and DLB, accumulations of phosphorylated α-synuclein aggregates are mainly observed in neurons in the form of Lewy bodies (LBs) and Lewy neurites (LNs), while they are seen in oligodendrocytes as glial cytoplasmic inclusions (GCIs) in multiple system atrophy (MSA)
To examine how neuronal cells take up α-synuclein fibrils and how the fibrils induce endogenous α-synuclein aggregates, we injected α-synuclein pre-formed fibrils (PFFs) into mouse brains and followed the induction of seed-dependent aggregation of α-synuclein

Summary

Introduction

Accumulation of phosphorylated α-synuclein aggregates has been implicated in several diseases, such as Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), and is thought to spread in a prion-like manner. These results suggest that extracellular α-synuclein fibrils are taken up into the presynaptic region and seed-dependently convert the endogenous normal α-synuclein that is abundant there to an abnormal phosphorylated form, which is transported through the axon to the cell body In neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease (PD) and amyotrophic lateral sclerosis, the neurodegeneration is thought to be caused by the accumulation of abnormal protein aggregates characteristic of each d isease[1,2]. The abnormal α-synuclein deposits observed in the brains of individuals are accumulated as fibrous or filamentous forms with cross-β structures, existing in phosphorylated and partially ubiquitinated states[4] These abnormal α-synuclein species exhibit seeding activity for prion-like conversion, being similar in this respect to the infectious forms of prion protein causing Creutzfeldt–Jakob disease and bovine spongiform encephalopathy. These findings suggest that α-synuclein aggregates may spread through neural circuits

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Conclusion