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Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation

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Published on: June 26, 2018

Synthetic α-synuclein fibrils replicate in mice causing MSA-like pathology.

Domenic Burger^1,2, Marianna Kashyrina^3,4, Lukas van den Heuvel^1,2

¹Laboratory of Biological Electron Microscopy, Institute of Physics, School of Basic Science, EPFL, Lausanne, Switzerland.

|November 5, 2025

Summary

Synthetic alpha-synuclein fibrils (1B) replicate in vivo, causing Multiple-system atrophy (MSA)-like pathology. Their structures mimic patient-derived fibrils, offering insights into disease mechanisms and potential therapies.

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Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo

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Published on: June 2, 2019

Area of Science:

Neuroscience
Biochemistry
Pathology

Background:

Multiple-system atrophy (MSA) is a fatal neurodegenerative disease characterized by alpha-synuclein (aSyn) inclusions.
The prion-like replication of aSyn fibrils and their in vivo GCI induction remain incompletely understood.
Synthetic fibril strain 1B shows promise for modeling MSA but requires atomic-level structural investigation.

Purpose of the Study:

To structurally characterize the synthetic fibril strain 1B and its in vivo propagated form (1B^P).
To investigate the in vivo self-replication and GCI-inducing capacity of 1B.
To elucidate the structural basis of MSA-like pathology induced by synthetic aSyn fibrils.

Main Methods:

High-resolution structural analyses (e.g., cryo-EM) of 1B and 1B^P fibrils.
In vivo studies involving injection of 1B into mice to assess GCI formation and pathology.
Structural comparison of 1B/1B^P with patient-derived MSA fibrils.

Main Results:

Synthetic 1B fibrils self-replicate in vivo, inducing Multiple-system atrophy (MSA)-like glial cytoplasmic inclusions (GCIs).
The structures of 1B and 1B^P fibrils are highly similar and resemble aSyn folds found in MSA patient fibrils.
Re-injection of propagated 1B^P fibrils into new mice recapitulated the MSA-like pathology.

Conclusions:

Conformational templating of aSyn enables fibril strain replication and MSA-like pathology in vivo.
The synthetic fibril strain 1B acts as a potent seed for inducing MSA-like pathology.
Structural insights into 1B and 1B^P provide a foundation for developing targeted therapeutic strategies for MSA.