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

Información del proyecto

CorticALS

Identificador del acuerdo de subvención: 639737

DOI

10.3030/639737

Proyecto cerrado

Fecha de la firma de la CE 24 Marzo 2015

Fecha de inicio 1 Abril 2015

Fecha de finalización 31 Marzo 2021

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 500 000,00

Aportación de la UE

€ 1 500 000,00

Coordinado por

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)

Período documentado: 2019-10-01 hasta 2021-03-31

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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.