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

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.