Amyotrophic Lateral Sclerosis from a cortical perspective: towards alternative therapeutic strategies

Projektinformationen

CorticALS

ID Finanzhilfevereinbarung: 639737

DOI

10.3030/639737

Projekt abgeschlossen

EK-Unterschriftsdatum 24 März 2015

Startdatum 1 April 2015

Enddatum 31 März 2021

Finanziert unter

• EXCELLENT SCIENCE - European Research Council (ERC)

Gesamtkosten

€ 1 500 000,00

EU-Beitrag

€ 1 500 000,00

Koordiniert durch

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 4 - CorticALS (Amyotrophic Lateral Sclerosis from a cortical perspective: towards alternative therapeutic strategies)

Berichtszeitraum: 2019-10-01 bis 2021-03-31

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

Amyotrophic Lateral Sclerosis (ALS) is the most common adult-onset neurodegenerative disease of the motor system, with a prevalence of 2-3/100 000. In spite of intensive research efforts, ALS remains an incurable disease and presents with a very severe prognosis, leading to death within 2 to 5 years following first motor symptoms.
At the cellular level, ALS is characterized by the combined degeneration of both upper motor neurons in the cerebral cortex (UMN), and lower motor neurons (LMN) in the medulla and spinal cord. This dual impairment allows discriminating ALS from other, less severe diseases affecting either UMN or LMN. Despite this precise clinical description, preclinical studies have so far mostly concentrated on LMN, leaving aside the role of UMN and of the cerebral cortex in ALS.
We aimed at deciphering the role of the cerebral cortex in ALS onset and progression, uravelling the molecular mechanisms behind UMN degeneration, and test strategies to replace the loss UMN.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

The work demonstrated that subpopulations of UMN start degenerating long before appearance of the first motor symptoms, suggesting that the cerebral cortex may contribute to diease onset.

Using mouse genetics, we demonstrated that, as opposed to LMN, UMN degenerate in a cell-autonomous manner. Molecular analyses of purified UMN demonstrated that their dysfunction is likely to start extremely early in the disease process and involves alteration of the metabolism of ARN, that ultimately leads to altered splicing of genes involved in neurnal excitability and activity. This suggests that cortical network dysfunction may be at play early on in the disease process.

Genetic disconnection between the cerebral cortex (absence of UMN and other subcerebral prohjetcion neurons) delays disease onset an dprogression, while maintenance of healthy UMN on the other hand had no impact on disease onset and progression. This suggests that the cerebral cortex displays toxic effect onto its targets, that are mediated by its corticogfugal connections.

Finally our experiments suggest that, in mouse models of ALS, the toxicity of the cerebral cortex on its targets is likely not mediated by the prion-like propagation of misfolded proteins, but may rather arise from cortical neuronal dysfunction and altered corticofugal (incluning UMN) excitability and activity.

In its whole, this project demonstrated the early and deleterious contribution of the cerebral cortex, UMN and other related subcerebral projection neurons to ALS, excluded one mechanism of corticofugal propagation and supported the possibility that cortical network dysfunction may contribute to disease onset and progression. It also unravelled molecular mechanisms that can now be targeted for therapeutic development.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

The projet contributed to shed light on the role of the cerebral cortex and its corticofugal neruonal populations on ALS onset and progression, and unraveled molecular mechanisms that can now be targeted in the context of therapeutic development.