Responsabile scientifico

• COTELLA Diego

Partecipanti al progetto

• COTELLA Diego
• ESPINOZA Stefano Luigi

Titolo del progetto

• Decoding dysfunctional RNA transcription and processing by dominant haploinsufficiency in Autism Spectrum Disorders (ASD): rescue by SINEUP translational regulators.

Ente finanziatore

• MUR - Ministero dell'Università e Ricerca

Programma di finanziamento

• PRIN - Progetti di Ricerca di Rilevante Interesse Nazionale (dal 2020)

Bando di riferimento

• PRIN 2022 PNRR

Anno di presentazione del progetto

• 2022

Anno di approvazione del progetto

• 2023

Project ID / numero contratto

• P2022RLE7Z_002

Durata del progetto

• 24 mesi

Inizio del progetto

• 30/11/2023

Fine del progetto

• 29/11/2025

Ente capofila

• UNITN - Università degli studi di Trento

Progetto approvato - Contributo unità di ricerca del Dipartimento

• €88.272,00

Sustainable Development Goals - Agenda 2030

Keyword

• Genetic risk factors
• Transcriptional dysregulation
• Non-coding RNAs
• SINEUP-translation activators
• Autism Spectrum Disorders (ASD)
• Alternative splicing and back-splicing

Stato del progetto

• Approvato

Abstract

• Autism spectrum disorder (ASD) is a genetically heterogeneous neurodevelopmental disorder. Most of the known ASD risk genes harbor de novo mutations that are likely causing haploinsufficiency. ASD susceptibility genes are predominantly associated to ‘dominant haploinsufficiencies’ (DHIs), in which the loss/inactivation of one copy of the gene carries significant risk for ASD. Although exome sequencing analysis has so far indicated mostly non-overlapping genes, these might perturb connected biological pathways. Previous studies, in fact, have shown molecular convergence at transcriptomic and epigenetic level in post-mortem brain tissue from ASD subjects. Abnormal patterns of RNA splicing was also previously reported in ASD, although not deeply investigated. RNA splicing could be particularly relevant for brain development and physiology, since alternative splicing (AS) is really prevalent in the brain. Notably, AS regulation is also crucial to the biogenesis of circular RNAs (circRNAs), stable non-coding RNAs produced by the circularization of exons. Thousands of circRNAs have been identified, preferentially expressed in the brain, and enriched at synapses. Although they were implicated in neurological diseases, circRNAs remain neglected in ASD. We therefore propose to reframe the study of molecular convergence in ASD, directly assessing the impact of Loss-of-Function (LoF) mutations in the most highly replicated risk factors not only on transcription, but specifically on neuronal linear and back-splicing. This approach has the potential to disclose a new and more complex scenario of molecular convergence in ASD, unveiling possible new therapeutic targets. Given that most of the currently known mutations in ASD risk genes are disruptive, usually affecting only one allele, a potential therapeutic avenue resides in stimulating the expression from the non-mutant allele to restore the protein to physiological levels. In this project, we will exploit the modular architecture of SINEUPs - a new functional class of non-coding RNAs molecules able to increase target protein levels. Their modular structure can be artificially engineered to create synthetic SINEUPs to increase translation of virtually any gene. In our recent investigations, we targeted the chromodomain helicase DNA-binding 8 (CHD8), one of the strongest risk factors for ASD. We employed synthetic SINEUP-CHD8 to efficiently stimulate endogenous CHD8 protein production, rescuing in vitro and in vivo molecular phenotypes. Thus, building on these promising results, here, we want to synthesize new active SINEUPs targeting other strong SD risk factors to revert transcriptional, linear and back-splicing phenotypes caused by DHIs. This will provide a strong Proof-of-Concept towards the development of a novel NA-based therapy for neurodevelopmental syndromes caused by protein haploinsufficiency.