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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El-Battari , A , Rodriguez , L , Chahinian , H , Delezay , O , Fantini , J , Yahi , N & Di Scala , C 2021 , ' 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 , vol. 22 , no. 21 , 11550 . https://doi.org/10.3390/ijms222111550

Title: Gene Therapy Strategy for Alzheimer's and Parkinson's Diseases Aimed at Preventing the Formation of Neurotoxic Oligomers in SH-SY5Y Cells
Author: El-Battari, Assou; Rodriguez, Lea; Chahinian, Henri; Delezay, Olivier; Fantini, Jacques; Yahi, Nouara; Di Scala, Coralie
Contributor organization: Neuroscience Center
Helsinki Institute of Life Science HiLIFE
Date: 2021-11
Language: eng
Number of pages: 15
Belongs to series: International Journal of Molecular Sciences
ISSN: 1422-0067
DOI: https://doi.org/10.3390/ijms222111550
URI: http://hdl.handle.net/10138/337320
Abstract: We present here a gene therapy approach aimed at preventing the formation of Ca2+-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 beta-amyloid peptide (A beta, Alzheimer) and alpha-synuclein (alpha-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 Ca2+ 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 A beta or alpha-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.
Subject: amyloid proteins
oligomeric pores
calcium
gangliosides
ALPHA-SYNUCLEIN OLIGOMERS
A-BETA OLIGOMERS
IN-VIVO
CHANNEL FORMATION
PLASMA-MEMBRANE
PROTEIN
BRAIN
GANGLIOSIDES
NEURODEGENERATION
MECHANISMS
1182 Biochemistry, cell and molecular biology
3112 Neurosciences
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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