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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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/21/11550 |
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| 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 |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-10T06:02:03Z |
| format | Article |
| id | doaj.art-cfcd4cf4f97b44cfbbb6ba7ca40c603c |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:02:03Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cfcd4cf4f97b44cfbbb6ba7ca40c603c2023-11-22T20:54:02ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-10-0122211155010.3390/ijms222111550Gene Therapy Strategy for Alzheimer’s and Parkinson’s Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y CellsAssou El-Battari0Léa Rodriguez1Henri Chahinian2Olivier Delézay3Jacques Fantini4Nouara Yahi5Coralie Di Scala6INSERM UMR_S 1072, Aix-Marseille Université, 13015 Marseille, FranceCUO-Recherche, Département d’ophtalmologie, Faculté de Médecine, Université Laval and Centre de recherche du CHU de Québec-Université Laval, Québec, QC G1V 0A6, CanadaINSERM UMR_S 1072, Aix-Marseille Université, 13015 Marseille, FranceFaculté de Médecine, SAINBIOSE INSERM U1059, Campus Santé Innovations, 42270 St. Priest en Jarez, FranceINSERM UMR_S 1072, Aix-Marseille Université, 13015 Marseille, FranceINSERM UMR_S 1072, Aix-Marseille Université, 13015 Marseille, FranceNeuroscience Center—HiLIFE, Helsinki Institute of Life Science, University of Helsinki, 00014 Helsinki, FinlandWe 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.https://www.mdpi.com/1422-0067/22/21/11550amyloid proteinsoligomeric porescalciumgangliosides |
| spellingShingle | 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 International Journal of Molecular Sciences amyloid proteins oligomeric pores calcium gangliosides |
| title | 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_short | 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 |
| topic | amyloid proteins oligomeric pores calcium gangliosides |
| url | https://www.mdpi.com/1422-0067/22/21/11550 |
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