Fondazione Telethon and Unione Italiana Lotta alla Distrofia Muscolare, a successful partnership for neuromuscular healthcare research of value for patients.

In 2001, Fondazione Telethon and the Italian muscular dystrophy patient organisation Unione Italiana Lotta alla Distrofia Muscolare joined their efforts to design and launch a call for grant applications specifically dedicated to clinical projects in the field of neuromuscular disorders. This strategic initiative, run regularly over the years and still ongoing, aims at supporting research with impact on the daily life of people with a neuromuscular condition and is centred on macro-priorities identified by the patient organisation. It is investigator-driven, and all proposals are peer-reviewed for quality and feasibility. Over the years, this funding program contributed to strengthening the activities of the Italian neuromuscular clinical network, reaching many achievements in healthcare research. Moreover, it has been an enabling factor for innovative therapy experimentation at international level and prepared the clinical ground to make therapies available to Italian patients. The ultimate scope of healthcare research is to ameliorate the delivery of care. In this paper, the achievements of the funded studies are analysed also from this viewpoint, to ascertain to which extent they have fulfilled the original goals established by the patient organisation. The evidence presented indicates that this has been a highly fruitful program. Factors that contributed to its success, lessons learned, challenges, and issues that remain to be addressed are discussed to provide practical examples of an experience that could inspire also other organizations active in the field of rare disease research.

A second pathway to degrade pyrimidine nucleic acid precursors in eukaryotes.

Pyrimidine bases are the central precursors for RNA and DNA, and their intracellular pools are determined by de novo, salvage and catabolic pathways. In eukaryotes, degradation of uracil has been believed to proceed only via the reduction to dihydrouracil. Using a yeast model, Saccharomyces kluyveri, we show that during degradation, uracil is not reduced to dihydrouracil. Six loci, named URC1-6 (for uracil catabolism), are involved in the novel catabolic pathway. Four of them, URC3,5, URC6, and URC2 encode urea amidolyase, uracil phosphoribosyltransferase, and a putative transcription factor, respectively. The gene products of URC1 and URC4 are highly conserved proteins with so far unknown functions and they are present in a variety of prokaryotes and fungi. In bacteria and in some fungi, URC1 and URC4 are linked on the genome together with the gene for uracil phosphoribosyltransferase (URC6). Urc1p and Urc4p are therefore likely the core components of this novel biochemical pathway. A combination of genetic and analytical chemistry methods demonstrates that uridine monophosphate and urea are intermediates, and 3-hydroxypropionic acid, ammonia and carbon dioxide the final products of degradation. The URC pathway does not require the presence of an active respiratory chain and is therefore different from the oxidative and rut pathways described in prokaryotes, although the latter also gives 3-hydroxypropionic acid as the end product. The genes of the URC pathway are not homologous to any of the eukaryotic or prokaryotic genes involved in pyrimidine degradation described to date.