Dottoressa di ricerca

ciclo: XXXVI

supervisore: Laura Ciapponi
relatore: Giovanni Cenci
co-supervisore: Gianluca Cestra

Titolo della tesi: RAN translated proteins in Myotonic Dystrophy type 2 cause locomotor defects and neuronal degeneration in Drosophila melanogaster

Myotonic dystrophies (DM) are rare inherited neuromuscular disorders linked to expansions of unstable microsatellite in non-coding regions of ubiquitously expressed genes. Myotonic Dystrophy type 2 (DM2) is caused by the expansion of a CCTG tetranucleotide repeat sequence in the CNBP gene. These expansions trigger molecular processes involving loss-of-function and gain-of-function mechanisms at DNA, RNA and protein levels. In our study, we explored the toxicity of RNA repeats that lead to a non-canonical repeat-associated non-AUG (RAN) translation. This process generates two toxic tetrapeptide repeat proteins (TPRs), PACL and QAGR, whose contribution to disease pathogenesis is still not completely clarified. We have generated transgenic Drosophila models expressing tagged PACL or QAGR peptide repeats under the UAS enhancer. The expression of these tetrapeptide repeats reduces fly viability and leads to phenotypic or behavioral alterations, including changes in eye and wing morphology and impairment of locomotor abilities. Interestingly, both phenotypic analysis and subcellular localization experiments have revealed distinct outcomes for PACL and QAGR TPR expression. In Drosophila larval brain cells, QAGR repeats exhibit primarily nuclear localization and are associated to increased levels of the autophagy regulator Ref(2)P (fly ortholog of p62). In contrast, PACL repeats does not affect Ref(2)P, but displays an association with stress granule formation, as evidenced by the genetic interaction with ROX8, which encodes the Drosophila counterpart of the stress granule marker TIAR. Accordingly, in human cells PACL repeats form aggregates that colocalize with TIAR, while arginine rich QAGR repeats are specifically enriched in the nucleolus. These findings strongly suggest that alterations in autophagy levels, caused by QAGR repeats, and stress granule formation, induced by PACL repeats, may together contribute to DM2 pathogenesis.

Produzione scientifica

11573/1691148 - 2023 - Modeling myotonic dystrophy type 2 using Drosophila melanogaster
Marzullo, Marta; Coni, Sonia; De Simone, Assia; Canettieri, Gianluca; Ciapponi, Laura - 01a Articolo in rivista
rivista: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (Basel: MDPI Center) pp. 14182-14194 - issn: 1422-0067 - wos: WOS:001073894300001 (0) - scopus: 2-s2.0-85173034988 (0)

11573/1694143 - 2023 - C9orf72 Toxic Species Affect ArfGAP-1 Function
Rossi, Simona; Di Salvio, Michela; Balì, Marilisa; De Simone, Assia; Apolloni, Savina; D'ambrosi, Nadia; Arisi, Ivan; Cipressa, Francesca; Cozzolino, Mauro; Cestra, Gianluca - 01a Articolo in rivista
rivista: CELLS (Basel: mdpi-Molecular Diversity Preservation International) pp. - - issn: 2073-4409 - wos: WOS:001046190200001 (0) - scopus: 2-s2.0-85167566264 (0)

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