Abstract

The pathogenesis of amyotrophic lateral sclerosis (ALS) and the molecular mechanisms behind its clinical heterogeneity are a major focus of research. The lack of a full understanding of the molecular changes driving the disease progression limits our ability to develop novel therapeutic strategies. It does also affect the rate of success of clinical trials, where lack of biomarkers of treatment response and of knowledge of the most effective therapeutic targets have conditioned the failure of more than 200 studies. The work presented is about the dissection of molecular mechanisms involved in inflammation, metabolism, senescence and relevant to cytoskeletal integrity, which have been identified as major drivers of disease
progression in ALS. Novel biomarkers of disease progression as well as therapeutic strategies have been formulated on the basis of proteomic experiments which have looked at the tissue/fluid interface in individuals with a significant difference in
prognosis and survival at different time points in the disease progression. Along with neurofilaments which have already been used for disease stratification, other makers involved in the humoral response to axonal proteins and in axonal regeneration hold promise as biomarkers and therapeutic targets for ALS.