Linking tryptophan catabolism to amyotrophic lateral sclerosis: from the pathogenesis to the pharmacological treatment (PRIN 2017)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease, whose pathogenic mechanisms are still largely unknown; detrimental neuroinflammation, driven by activated resident microglial and infiltrating leukocytes, appears as one of the major features of this pathology. Tryptophan (Trp) catabolism represents a well-known mechanism of modulation of the immune response, for the manteinance of immune homeostasis and to ensure the tolerance towards self antigens. Recent evidence suggests that an altered tryptophan metabolism could represent one of the pathogenetic mechanisms underlying the onset and/or progression of ALS. Trp metabolism is activated not only in eukaryotic cells, but also in resident bacteria colonizing the gastrointestinal tract of mammalian hosts, the so-called microbiota. Recent evidences showed an altered gut composition (dysbiosis) in a murine model of ALS, together with an impaired gut structure. Thus, alterations in the Trp catabolism, not only in host, but also in microbiota cells, subsequently leading to the aberrant production of specific Trp metabolites, could represent a potential target of intervention for the control of the disease progression. Thus, a deep investigation of alterations in Trp catabolism as a major pathogenetic mechanism of ALS, and the correlation between Trp metabolism and pharmacological effects, are the major goals of the present proposal.