Selection of DNA aptamers that prevent the fibrillization of α-synuclein protein in cellular and mouse models.

Autor:	McConnell EM; Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada., Chan D; Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada., Ventura K; Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada., Callahan JP; Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada., Harris K; Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada., Hunt VH; Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada., Boisjoli S; Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada., Knight D; Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada., Monk ET; Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada., Holahan MR; Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada., DeRosa MC; Department of Chemistry, Carleton University, Ottawa, ON K1S 5B6, Canada.; Institute of Biochemistry, Carleton University, Ottawa, ON K1S 5B6, Canada.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2024 Jun 15; Vol. 35 (3), pp. 102251. Date of Electronic Publication: 2024 Jun 15 (Print Publication: 2024).
DOI:	10.1016/j.omtn.2024.102251
Abstrakt:	A neuropathological hallmark of Parkinson's disease (PD) is the aggregation and spreading of misfolded α-synuclein (αSyn) protein. In this study, a selection method was developed to identify aptamers that showed affinity for monomeric αSyn and inhibition of αSyn aggregation. Aptamer a-syn-1 exhibited strong inhibition of αSyn aggregation in vitro by transmission electron microscopy and Thioflavin T fluorescence. A-syn-1 -treated SH-SY5Y cells incubated with pre-formed fibrils (PFFs) showed less intracellular aggregation of αSyn in comparison with a scrambled oligonucleotide control, as observed with fluorescent microscopy. Systemic delivery of a-syn-1 to the brain was achieved using a liposome vehicle and confirmed with fluorescence microscopy and qPCR. Transgenic mice overexpressing the human A53T variant of αSyn protein were injected with a-syn-1 loaded liposomes at 5 months of age both acutely (single intraperitoneal [i.p.] injection) and repeatedly (5 i.p. injections over 5 days). Western blot protein quantification revealed that both acute and repeated injections of a-syn-1 decreased levels of the aggregated form of αSyn in the transgenic mice in the prefrontal cortex, caudate, and substania nigra (SNc). These results provide in vitro and in vivo evidence that a-syn-1 can inhibit pathological αSyn aggregation and may have implications in treatment strategies to target dysregulation in PD. Competing Interests: M.C.D. is a section editor of Molecular Therapy - Nucleic Acids. The authors have a patent related to this work: WO2019079887A1. It is entitled: Aptamers as a therapeutic tool to prevent protein aggregation in neurodegenerative disease. (© 2024 Published by Elsevier Inc. on behalf of The American Society of Gene and Cell Therapy.)
Databáze:	MEDLINE
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