Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells

We present here a gene therapy approach aimed at preventing the formation of Ca<sup>2+</sup>-permeable amyloid pore oligomers that are considered as the most neurotoxic structures in both Alzheimer’s and Parkinson’s diseases. Our study is based on the design of a small peptide inhibitor...

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Autores principales:	Assou El-Battari, Léa Rodriguez, Henri Chahinian, Olivier Delézay, Jacques Fantini, Nouara Yahi, Coralie Di Scala
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	amyloid proteins oligomeric pores calcium gangliosides Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/cfcd4cf4f97b44cfbbb6ba7ca40c603c
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spelling	oai:doaj.org-article:cfcd4cf4f97b44cfbbb6ba7ca40c603c2021-11-11T17:01:34ZGene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells10.3390/ijms2221115501422-00671661-6596https://doaj.org/article/cfcd4cf4f97b44cfbbb6ba7ca40c603c2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11550https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067We present here a gene therapy approach aimed at preventing the formation of Ca<sup>2+</sup>-permeable amyloid pore oligomers that are considered as the most neurotoxic structures in both Alzheimer’s and Parkinson’s diseases. Our study is based on the design of a small peptide inhibitor (AmyP53) that combines the ganglioside recognition properties of the β-amyloid peptide (Aβ, Alzheimer) and α-synuclein (α-syn, Parkinson). As gangliosides mediate the initial binding step of these amyloid proteins to lipid rafts of the brain cell membranes, AmyP53 blocks, at the earliest step, the Ca<sup>2+</sup> cascade that leads to neurodegeneration. Using a lentivirus vector, we genetically modified brain cells to express the therapeutic coding sequence of AmyP53 in a secreted form, rendering these cells totally resistant to oligomer formation by either Aβ or α-syn. This protection was specific, as control mCherry-transfected cells remained fully sensitive to these oligomers. AmyP53 was secreted at therapeutic concentrations in the supernatant of cultured cells, so that the therapy was effective for both transfected cells and their neighbors. This study is the first to demonstrate that a unique gene therapy approach aimed at preventing the formation of neurotoxic oligomers by targeting brain gangliosides may be considered for the treatment of two major neurodegenerative disorders, Alzheimer’s and Parkinson’s diseases.Assou El-BattariLéa RodriguezHenri ChahinianOlivier DelézayJacques FantiniNouara YahiCoralie Di ScalaMDPI AGarticleamyloid proteinsoligomeric porescalciumgangliosidesBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11550, p 11550 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	amyloid proteins oligomeric pores calcium gangliosides Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	amyloid proteins oligomeric pores calcium gangliosides Biology (General) QH301-705.5 Chemistry QD1-999 Assou El-Battari Léa Rodriguez Henri Chahinian Olivier Delézay Jacques Fantini Nouara Yahi Coralie Di Scala Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells
description	We present here a gene therapy approach aimed at preventing the formation of Ca<sup>2+</sup>-permeable amyloid pore oligomers that are considered as the most neurotoxic structures in both Alzheimer’s and Parkinson’s diseases. Our study is based on the design of a small peptide inhibitor (AmyP53) that combines the ganglioside recognition properties of the β-amyloid peptide (Aβ, Alzheimer) and α-synuclein (α-syn, Parkinson). As gangliosides mediate the initial binding step of these amyloid proteins to lipid rafts of the brain cell membranes, AmyP53 blocks, at the earliest step, the Ca<sup>2+</sup> cascade that leads to neurodegeneration. Using a lentivirus vector, we genetically modified brain cells to express the therapeutic coding sequence of AmyP53 in a secreted form, rendering these cells totally resistant to oligomer formation by either Aβ or α-syn. This protection was specific, as control mCherry-transfected cells remained fully sensitive to these oligomers. AmyP53 was secreted at therapeutic concentrations in the supernatant of cultured cells, so that the therapy was effective for both transfected cells and their neighbors. This study is the first to demonstrate that a unique gene therapy approach aimed at preventing the formation of neurotoxic oligomers by targeting brain gangliosides may be considered for the treatment of two major neurodegenerative disorders, Alzheimer’s and Parkinson’s diseases.
format	article
author	Assou El-Battari Léa Rodriguez Henri Chahinian Olivier Delézay Jacques Fantini Nouara Yahi Coralie Di Scala
author_facet	Assou El-Battari Léa Rodriguez Henri Chahinian Olivier Delézay Jacques Fantini Nouara Yahi Coralie Di Scala
author_sort	Assou El-Battari
title	Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells
title_short	Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells
title_full	Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells
title_fullStr	Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells
title_full_unstemmed	Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells
title_sort	gene therapy strategy for alzheimer’s and parkinson’s diseases aimed at preventing the formation of neurotoxic oligomers in sh-sy5y cells
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/cfcd4cf4f97b44cfbbb6ba7ca40c603c
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Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells

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