From stress to Amyotrophic Lateral Sclerosis mechanobiology: featuring Piezo1 in Motor Neuron Disease

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, characterized in 97% of the cases by the accumulation of TDP-43 in cytoplasmic inclusions. As there is an association between oxidative and mechanical stress and ALS, we aimed this thesis to unveil the interrelationship between these three factors. We proved that the mechanosensitive Piezo1 channel is expressed and can be mechanically activated in murine lower motor neurons. Next, we observed a bidirectional relationship between Piezo1 and oxidative stress. H2O2 increases the activity and expression of Piezo1 through the alteration of its inactivation dynamics and the integrated stress response (ISR), and Piezo1 activation induces ISR activation. We demonstrated that Piezo1 overactivation induces the cytoplasmatic translocation and aggregation of TDP-43 through ISR and nuclear pore complex disruption, two molecular markers of ALS. Finally, using in-silico modelling, we have proposed a list of more than 400 ISR downstream candidates with a high specificity and related them with synaptoplasticity and neurodegeneration pathways. In conclusion, we propose the interrelationship between Piezo1 and ISR as a novel therapeutic target for ALS.