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

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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.
Funding Information
  • Japan Society for the Promotion of Science (21K07288)
  • Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
  • Takeda Science Foundation
  • Core Research for Evolutional Science and Technology (JPMJCR18H3)
  • Japan Agency for Medical Research and Development (JP18dm0207019)

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