ALS disease progression from disease onset to endstage can vary between few months and more than a decade, even in the presence of same genetic mutation. This makes difficult any treatment response in clinical trials in absence of reliable prognostic factors. We have evidence that the acetylcholine receptor (AChR) and muscle regeneration contributes significantly to the variability in the disease progression in ALS patients and in two mSOD1 mice. We also showed that changes in the composition of AChR subunits in muscles of patients well discriminate ALS from pure muscle denervation. Moreover, treatment with palmitoylethanolamide (PEA), a PPAR alpha acting drug, contributes to the maintenance of endplates and improved muscle force and respiration in ALS patients by promoting the stability of AChRs.
Given that strategies aimed to preserve motor neuron (MN) failed or modestly improve the disease progression in ALS patients and mouse models, here, we propose to investigate deeper the AChRs and skeletal muscles of patients and mouse models with different disease progression, to uncover pharmacological targets for ALS therapy.
This project aims to: i) characterize the changes in the function of AChRs in both ALS patients and mice with different disease progression; ii) verify the impact of the AChRs pathway (Agrin-MusK) as well as the muscle regenerative process (Pax7-MyoD) modulation on the disease course in fast progressing ALS patients and mSOD1 mice. The overlap between patients and animal models will allow to further investigate the aberrant processes leading to muscle denervation atrophy. At the end of the project we expect to strengthen our knowledge about ALS pathophysiology and to produce a combination of NMJ-related molecular signatures that will be predictive of the difference in disease progression.
