Creazione di un nuovo modello di C. Elegans per studiare i disturbi neurogenetici del decadimento dell'mRNA mediato da sciocchezze in H. Sapiens

Neurological diseases of genetic origin severely burden patients, their families that support them, and the healthcare systems that treat them. When the disease mechanism is not quite understood, it adds an additional challenge to finding a therapeutic approach to manage the illness. Currently, no known cures exist for most of these disorders and treatment is provided on a case-by-case basis to mitigate symptoms. Therefore, deep knowledge of the underlying molecular mechanisms is critical to develop translational approaches capable of providing novel therapeutic options. Work performed by different clinical genetics groups, including our collaborators, has found that mutations in the UPF-1 gene may lead to a severe neurological syndrome characterized by global developmental delay, language impairment, intellectual disability, seizure, hypotonia, glaucoma and cataracts. UPF-1 is a crucial component of the nonsense mediated decay (NMD) pathway, which ensures a high fidelity of mRNA transcripts. However, it is currently not clear how the identified mutations contribute to produce the observed symptoms. We investigated this problem using the genetically tractable model of Caenorhabditis elegans, whose smg-2 gene is a close homolog of UPF-1. Our observations suggest that the total loss-of-function of the smg-2 gene is required for development of a normal neuronal network, since smg-2 mutants show distinct defects in locomotion, behaviour and neuroanatomy.