🧠 When a Synthetic Tiny Fiber Self-Replicates in the Brain

Multiple system atrophy (MSA) is a rare and severe neurodegenerative disease, caused by the massive and rapid accumulation of α-synuclein fibrils in the brain. This accumulation is observed in other synucleinopathies like Parkinson's disease and Lewy body dementia, but with a much slower rate of progression.

The key remaining question: what gives some fibrils the ability to spread with the speed of infectious agents, while others evolve much more slowly over many years?


To answer this, scientists created a specific α-synuclein fibril in the laboratory, named 1B, and injected it into the brains of mice. This synthetic entity induced the very rapid appearance of pathological inclusions similar to those observed in MSA. The results of this study, published in the journal Nature, provide new insight into the mechanisms of propagation of synucleinopathies.

Self-Replication Observed at the Atomic Scale

Using cryo-electron microscopy, which allows the study of protein structure at the atomic scale, scientists observed the synthetic fibrils before inoculation (1B) and those produced in the brain as a result of inoculation (1BP). The two structures proved to be almost identical.

1BP retains the same folding, pairing, and stacking architecture as 1B. This similarity demonstrates that the synthetic fibril 1B generated its own copy within the organism, a process that corresponds to genuine self-replication in vivo. The existence of such a phenomenon had never been demonstrated at the atomic scale in animals until now, not even for prions. Furthermore, diluted brain homogenates from mice containing these 1BP fibrils can in turn transmit the pathology to other animals through reinjection.

Towards a Better Understanding and New Therapeutic Strategies

Scientists have also identified particular structural regions that seem to play a central role in these fibrils' ability to multiply and evade cellular degradation systems.

"This work provides experimental proof that a conformational replicative mechanism - of the prion type - is at work in synucleinopathies," emphasizes François Ichas. "It opens up prospects for understanding how certain forms of alpha-synuclein assembly become pathogenic and for designing strategies aimed at interrupting this process."

This work provides a robust experimental model of the prion-like mechanisms underlying MSA and other synucleinopathies, such as Parkinson's disease or Lewy body dementia. It also sheds light on the supramolecular structural bases that differentiate these pathologies.

In the longer term, identifying the critical interfaces exposed by 1B fibrils could guide the design of inhibitors capable of preventing their spread. This discovery also invites us to rethink the boundaries between biological entities and artificial pathogenic agents.