{"id":189318,"date":"2025-11-05T17:03:32","date_gmt":"2025-11-05T16:03:32","guid":{"rendered":"https:\/\/www.bordeaux-neurocampus.fr\/?p=189318"},"modified":"2025-11-05T17:52:38","modified_gmt":"2025-11-05T16:52:38","slug":"when-a-synthetic-fibril-self%e2%80%91replicates-in-the-brain","status":"publish","type":"post","link":"https:\/\/www.bordeaux-neurocampus.fr\/en\/when-a-synthetic-fibril-self%e2%80%91replicates-in-the-brain\/","title":{"rendered":"When a Synthetic Fibril Self\u2011Replicates in the Brain"},"content":{"rendered":"

Multiple system atrophy (MSA) is a rare, incurable neurodegenerative disease marked by intracellular inclusions composed of alpha\u2011synuclein fibrils. In a paper published in Nature<\/em>, scientists show that a particular model of alpha\u2011synuclein fibril created artificially in vitro can self\u2011replicate and proliferate in the mouse brain, recapitulating the intracerebral inclusions seen in the human disease. These results open new avenues for understanding prion\u2011like mechanisms and for designing novel inhibitors.<\/strong><\/p>\n

An experiment to understand how pathogenic fibrils spread in the brain<\/h3>\n

Multiple system atrophy (MSA) is a rare and severe neurodegenerative disease caused by the massive, rapid accumulation of \u03b1\u2011synuclein fibrils in the brain. This accumulation is also observed in other synucleinopathies such as Parkinson\u2019s disease and dementia with Lewy bodies, but with a much slower rate of progression. The key question that remains is: what gives certain fibrils the ability to spread with the speed of infectious agents, while others evolve much more slowly over many years?<\/p>\n

To address this, scientists created in the laboratory a specific \u03b1\u2011synuclein fibril, dubbed 1B, and injected it into the brains of mice. This synthetic entity very rapidly induced pathological inclusions similar to those observed in MSA. The results of this study, published in Nature<\/em>, shed new light on the mechanisms by which synucleinopathies propagate.<\/p>\n

Self\u2011replication observed at atomic resolution<\/h3>\n

Using cryo\u2011electron microscopy, which makes it possible to study protein structures at atomic scale, the scientists examined 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 1B fibril generated its own copy in the organism\u2014a process that amounts to genuine in vivo self\u2011replication. The existence of such a phenomenon had never previously been demonstrated at atomic resolution in an animal, not even for prions. Moreover, diluted mouse\u2011brain homogenates containing these 1BP fibrils can in turn transmit the pathology to other animals upon reinjection.<\/p>\n

Toward a better understanding and new therapeutic strategies<\/h3>\n

The scientists also identified specific structural regions that appear to play a central role in these fibrils\u2019 ability to multiply and to evade cellular degradation systems.<\/p>\n

\u201cThese findings provide experimental proof that a conformational, prion\u2011like replicative mechanism is at work in synucleinopathies,<\/em>\u201d notes Fran\u00e7ois Ichas. \u201cThey open avenues for understanding how certain forms of \u03b1\u2011synuclein assembly become pathogenic and for designing strategies to interrupt this process<\/em>.\u201d<\/p>\n

This work provides a robust experimental model of the prion\u2011like mechanisms underlying MSA and other synucleinopathies, such as Parkinson\u2019s disease and dementia with Lewy bodies. It also highlights the supramolecular structural underpinnings that differentiate these disorders. 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 a rethinking of the boundaries between biological entities and artificially derived pathogenic agents.<\/p>\n

\"\"
The 1B (synthetic) and 1BP (formed in the brains of injected mice) \u03b1\u2011synuclein fibrils share an almost identical structure, evidence that 1B self\u2011replicates in vivo. The three\u2011dimensional structures of 1B and 1BP can be explored on the RCSB Protein Data Bank (rcsb.org) under accession codes 9EUU and 9RZF, respectively.<\/figcaption><\/figure>\n

Reference<\/h3>\n

Synthetic \u03b1-synuclein fibrils replicate in mice causing MSA-like pathology
\n<\/strong><\/em>Domenic Burger, Marianna Kashyrina<\/strong>, Lukas van den Heuvel, Hortense de La Seigli\u00e8re<\/strong>, Amanda J. Lewis, Francesco De Nuccio, Inayathulla Mohammed, J\u00e9r\u00e9my Verch\u00e8re, C\u00e9cile Feuillie, M\u00e9lanie Berbon, Marie-Laure Arotcarena<\/strong>, Aude Retailleau<\/strong>, Erwan Bezard<\/strong>, Marie-H\u00e9l\u00e8ne Canron<\/strong>, Wassilios G. Meissner<\/strong>, Antoine Loquet, Luc Bousset, Christel Poujol<\/strong>, K. Peter, R. Nilsson, Florent Laferri\u00e8re<\/strong>, Thierry Baron, Dario Domenico Lofrumento, Francesca De Giorgi<\/strong>, Henning Stahlberg, Fran\u00e7ois Ichas<\/strong>
\n<\/strong><\/em>https:\/\/www.nature.com\/articles\/s41586-025-09698-1<\/a><\/p>\n

Contacts<\/h3>\n

Dr. Fran\u00e7ois Ichas<\/strong>
\nInstitut des Maladies Neurod\u00e9g\u00e9n\u00e9ratives CNRS Universit\u00e9 de Bordeaux, France
\nLaboratoire d\u2019Anatomie Humaine, DiSTeBA, Universit\u00e9 du Salento, Lecce, Italie.
\nfrancois.ichas@inserm.fr<\/a><\/p>\n

Prof. Henning Stahlberg,<\/strong>
\nLaboratoire de Microscopie Electronique Appliqu\u00e9e \u00e0 la Biologie, Ecole Polytechnique F\u00e9d\u00e9rale de Lausanne, Universit\u00e9 de Lausanne, Lausanne, Suisse.
\nhenning.stahlberg@epfl.ch<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"

Fran\u00e7ois Ichas in Nature<\/p>\n","protected":false},"author":108,"featured_media":189311,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[71],"tags":[],"class_list":["post-189318","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-highlight-en"],"_links":{"self":[{"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/posts\/189318","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/users\/108"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/comments?post=189318"}],"version-history":[{"count":6,"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/posts\/189318\/revisions"}],"predecessor-version":[{"id":189349,"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/posts\/189318\/revisions\/189349"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/media\/189311"}],"wp:attachment":[{"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/media?parent=189318"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/categories?post=189318"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bordeaux-neurocampus.fr\/en\/wp-json\/wp\/v2\/tags?post=189318"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}