ALS progression can vary widely even in the presence of the same genetic mutation. This makes difficult any evaluation of treatments
in the absence of reliable prognostic factors. We have evidence that changes in acetylcholine receptor (AChR) composition and muscle
regeneration contributes significantly to the variability in disease progression of two mSOD1 mice. 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.
Here, we propose to investigate deeper the AChRs and skeletal muscles of mouse models with different disease progression, to
uncover prognostic biomarkers and pharmacological targets for ALS therapy. This project aims to: i) characterize the changes in the
AChR subunits composition and their aggregating pathway (Agrin-MusK) as well as the muscle regenerative process (Pax7-MyoD), in
two ALS mouse models with different disease progression; ii) verify the impact of their modulation on the disease course in fast
progressing ALS mice.
The project is divided into two work packages and involves electrophysiological, immunohistopathological and biochemical analyses. The potential impact of the results is twice as it will allow investigating the aberrant processes leading to muscle denervation atrophy and will provide a proof of concept for disease-modifying treatment immediately translatable to patients. We expect to strengthen our knowledge about ALS pathophysiology and to produce a combination of NMJ-related molecular signatures predictive of the difference in disease progression for the stratification of patients to be recruited in clinical trials.
We anticipate that at the end of this project we will:
i) have a full understanding of the implication of AChR subunits and skeletal muscles in the pathophysiology and progression of ALS;
ii) identify novel therapeutic targets associated with NMJ and myofibers to be used alone or in combination with MN protective strategies in ALS therapy.
iii) identify prognostic biomarkers to stratify patients and identify clues of disease progression; The eventual overlapping between animals and humans will allow a rapid transfer of information to the clinical application. 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.