Stabilization of tRNAs as a therapeutic strategy for diseases due to mutations in mt-tRNAs.
Componente | Qualifica | Struttura | Categoria |
---|---|---|---|
Silvia Berni | Tecnico | Sapienza | Altro personale Sapienza o esterni |
Massimo Foschi | Tecnico | Sapienza | Altro personale Sapienza o esterni |
Mutations in genes coding for mitochondrial (mt)-tRNAs (MTTs) are responsible for a wide range of currently untreatable pathologies. We recently demonstrated that the carboxy-terminal domain (Cterm) of
human mt leucyl-tRNA synthetase (mt-LeuRS), and two peptides derived from it (ß30_31 and ß32_33), are able to rescue the defects caused by the two mt-tRNA mutations most frequently causing severe syndromes: the m.3243A>G in mt-tRNALeu(UUR) and the m.8344A>G in mt-tRNALys. We further demonstrated that these molecules directly interact with both mutant tRNAs and stabilize a wild-type like conformation of human mt-tRNALeu(UUR) in vitro. The rescuing activity appears therefore to be mediated by a chaperonic mechanism. These peptides are therefore attractive lead molecules for the development of therapeutic compounds against mt-tRNA mutations-related syndromes. In the frame of the global effort to translate these highly promising results into therapeutic applications, we aim to:
Develop strategies to deliver our chaperonic rescuing molecules, i.e., LeuRS-Cterm and ß32_33 peptide, which is more active than ß30_31, to the mt matrix, where they are to exert their therapeutic activity;
Analyze in detail the tissue-specific rescuing effect of the above molecules on cell models developed by our group (i.e. neurons and myotubes differentiated from induced pluripotent stem cells-iPSCs)