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.
ALS is a poor prognosis disease for which there is no cure yet. Current development of therapies is limited to long-duration and very costly studies. We think that the lack of an effective treatment for ALS is due to two reasons: i) the poor attention to the role of muscle denervation for identifying therapeutic targets; ii) the lack of biomarkers that allow the stratification of ALS patients in the clinical trials. With this project, we expect to fill the gap of knowledge regarding the role of NMJ and muscle function on development and progression of ALS.
Three main endpoints are expected from this project:
1) understanding the implication of muscle AChR subunits expression and function in the pathophysiology and progression of ALS;
2) identifying of prognostic biomarkers to stratify patients and identify clues of disease progression;
3) developing novel therapeutic strategies to target the NMJ and muscle fibers alterations to be used alone or combined with MN protective strategies in the ALS therapy.
The potential impact of the results is twice as it will provide the basis for the immediate transfer to clinical application in a large cohort of ALS patients. In addition, the overlap between patients and animal models will allow to further investigate the aberrant processes leading to NMJ impairment. At the end of the project, we expect to strengthen the knowledge about ALS pathophysiology, to produce a combination of NMJ-related molecular signatures that will be predictive of the difference in disease progression and to provide a proof of concept for disease modifying treatment.
This project is innovative because it addresses all these issues through the study of NMJs and muscle in ALS ALS patients and mice with different disease severity. The project innovation is also given by the multidisciplinary approaches (electrophysiology, biochemistry, molecular biology, histopathology) applied to patients and preclinical models and. By using this strategy, we will identify novel therapeutic targets of the disease.