CircHTT(2,3,4,5,6) - co-evolving with the HTT CAG-repeat tract - modulates Huntington's disease phenotypes.

Autor:	Morandell J; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Monziani A; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Lazioli M; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Donzel D; Institute of Biophysics Unit at Trento, National Research Council - CNR, 38123 Trento, Italy., Döring J; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Oss Pegorar C; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., D'Anzi A; Cellular Reprogramming Unit Fondazione IRCCS, Casa Sollievo Della Sofferenza, Viale dei Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy., Pellegrini M; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Mattiello A; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Bortolotti D; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Bergonzoni G; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Tripathi T; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Mattis VB; Board of Governor's Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Kovalenko M; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Rosati J; Cellular Reprogramming Unit Fondazione IRCCS, Casa Sollievo Della Sofferenza, Viale dei Cappuccini 1, 71013 San Giovanni Rotondo, FG, Italy., Dieterich C; Section of Bioinformatics and Systems Cardiology, University Hospital Heidelberg, 69120 Heidelberg, Germany., Dassi E; Laboratory of RNA Regulatory Networks, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy., Wheeler VC; Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA., Ellederová Z; Research Center PIGMOD, Institute of Animal Physiology and Genetics, Czech Academy of Science, 277 21 Libechov, Czech Republic., Wilusz JE; Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Therapeutic Innovation Center, Baylor College of Medicine, Houston, TX 77030, USA., Viero G; Institute of Biophysics Unit at Trento, National Research Council - CNR, 38123 Trento, Italy., Biagioli M; NeuroEpigenetics Laboratory, Department of Cellular, Computational, and Integrative Biology - CIBIO, University of Trento, 38123 Trento, Italy.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Jun 03; Vol. 35 (3), pp. 102234. Date of Electronic Publication: 2024 Jun 03 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102234
Abstrakt:	Circular RNA (circRNA) molecules have critical functions during brain development and in brain-related disorders. Here, we identified and validated a circRNA, circHTT(2,3,4,5,6) , stemming from the Huntington's disease (HD) gene locus that is most abundant in the central nervous system (CNS). We uncovered its evolutionary conservation in diverse mammalian species, and a correlation between circHTT(2,3,4,5,6) levels and the length of the CAG-repeat tract in exon-1 of HTT in human and mouse HD model systems. The mouse orthologue, circHtt(2,3,4,5,6) , is expressed during embryogenesis, increases during nervous system development, and is aberrantly upregulated in the presence of the expanded CAG tract. While an IRES-like motif was predicted in circH TT (2,3,4,5,6) , the circRNA does not appear to be translated in adult mouse brain tissue. Nonetheless, a modest, but consistent fraction of circHtt(2,3,4,5,6) associates with the 40S ribosomal subunit, suggesting a possible role in the regulation of protein translation. Finally, c ircHtt(2,3,4,5,6) overexpression experiments in HD-relevant ST Hdh striatal cells revealed its ability to modulate CAG expansion-driven cellular defects in cell-to-substrate adhesion, thus uncovering an unconventional modifier of HD pathology. Competing Interests: J.E.W. serves as a consultant for Laronde. V.C.W. was a founding scientific advisory board member with financial interest in Triplet Therapeutics Inc. Her financial interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. She is a scientific advisory board member of LoQus23 Therapeutics Ltd. and has provided paid consulting services to Acadia Pharmaceuticals Inc., Alnylam Inc., Biogen Inc., Passage Bio, and Rgenta Therapeutics. She has received research support from Pfizer Inc. (© 2024 The Author(s).)
Databáze:	MEDLINE
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