Effective lowering of α-synuclein expression by targeting G-quadruplex structures within the SNCA gene.

Autor: Pirota V; Department of Chemistry, University of Pavia, Pavia, Italy; G4-INTERACT, USERN, Pavia, Italy. Electronic address: valentina.pirota@unipv.it., Rey F; G4-INTERACT, USERN, Pavia, Italy; Pediatric Clinical Research Center 'Fondazione Romeo ed Enrica Invernizzi', Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; Center of Functional Genomics and Rare diseases, Buzzi Children's Hospital, Milan, Italy., Esposito L; Pediatric Clinical Research Center 'Fondazione Romeo ed Enrica Invernizzi', Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; Center of Functional Genomics and Rare diseases, Buzzi Children's Hospital, Milan, Italy., Fantini V; Laboratory of Neurobiology and Neurogenetic, Golgi-Cenci Foundation, Abbiategrasso, Italy., Pandini C; Department of Biosciences, University of Milan, Milan, Italy., Maghraby E; Center of Functional Genomics and Rare diseases, Buzzi Children's Hospital, Milan, Italy; Department of Biology and Biotechnology 'Lazzaro Spallanzani', University of Pavia, Pavia, Italy., Di Gerlando R; Department of Biology and Biotechnology 'Lazzaro Spallanzani', University of Pavia, Pavia, Italy; Molecular Biology and Transcriptomic Unit, IRCCS Mondino Foundation, Pavia, Italy., Doria F; Department of Chemistry, University of Pavia, Pavia, Italy., Mella M; Department of Chemistry, University of Pavia, Pavia, Italy., Pansarasa O; Cellular Models and Neuroepigenetics Unit, IRCCS Mondino Foundation, Pavia, Italy., Gandellini P; Department of Biosciences, University of Milan, Milan, Italy., Freccero M; Department of Chemistry, University of Pavia, Pavia, Italy., Carelli S; Pediatric Clinical Research Center 'Fondazione Romeo ed Enrica Invernizzi', Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy; Center of Functional Genomics and Rare diseases, Buzzi Children's Hospital, Milan, Italy. Electronic address: stephana.carelli@guest.unimi.it., Cereda C; Center of Functional Genomics and Rare diseases, Buzzi Children's Hospital, Milan, Italy.
Jazyk: angličtina
Zdroj: International journal of biological macromolecules [Int J Biol Macromol] 2024 Oct; Vol. 277 (Pt 4), pp. 134417. Date of Electronic Publication: 2024 Aug 03.
DOI: 10.1016/j.ijbiomac.2024.134417
Abstrakt: Alpha-synuclein, encoded by the SNCA gene, is a pivotal protein implicated in the pathogenesis of synucleinopathies, including Parkinson's disease. Current approaches for modulating alpha-synuclein levels involve antisense nucleotides, siRNAs, and small molecules targeting SNCA's 5'-UTR mRNA. Here, we propose a groundbreaking strategy targeting G-quadruplex structures to effectively modulate SNCA gene expression and lowering alpha-synuclein amount. Novel G-quadruplex sequences, identified on the SNCA gene's transcription starting site and 5'-UTR of SNCA mRNAs, were experimentally confirmed for their stability through biophysical assays and in vitro experiments on human genomic DNA. Biological validation in differentiated SH-SY5Y cells revealed that well-known G-quadruplex ligands remarkably stabilized these structures, inducing the modulation of SNCA mRNAs expression, and the effective decrease in alpha-synuclein amount. Besides, a novel peptide nucleic acid conjugate, designed to selectively disrupt of G-quadruplex within the SNCA gene promoter, caused a promising lowering of both SNCA mRNA and alpha-synuclein protein. Altogether our findings highlight G-quadruplexes' key role as intriguing biological targets in achieving a notable and successful reduction in alpha-synuclein expression, pointing to a novel approach against synucleinopathies.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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