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
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.
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.