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

Assou El-Battari,Olivier Delézay,Coralie Di Scala,Nouara Yahi,Henri Chahinian,Jacques Fantini,Léa Rodriguez

doi:10.3390/ijms222111550

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 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 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 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.

Highlights

Neurological disorders, including Alzheimer’s and Parkinson’s diseases (AD and PD, respectively), are currently the leading source of disability around the world, and their prevalence will continue to grow exponentially as the population ages [1,2]
AmyP53 prevents the generation of these neurotoxic oligomers at the earliest step [19,31,32], which is the binding of the amyloid protein (α-syn or Aβ) to ganglioside-enriched lipid rafts at the surface of brain cells [28]
AmyP53 is the first molecule that tackles gangliosides, prevents the formation of neurotoxic oligomers and is active against two amyloid proteins (α-syn and Aβ), including mutant forms that are responsible for inherited Parkinson and Alzheimer diseases [28,32]

Summary

Introduction

Neurological disorders, including Alzheimer’s and Parkinson’s diseases (AD and PD, respectively), are currently the leading source of disability around the world, and their prevalence will continue to grow exponentially as the population ages [1,2]. Insoluble aggregates of amyloid proteins have been considered as the main culprits in AD and PD [5]. This notion has been dismissed and, instead of these large aggregates, small oligomers of amyloid proteins, including β-amyloid peptide (Aβ) and α-synuclein (α-syn), are considered as the primary neurotoxic species in AD and PD [6,7,8,9,10,11]. Most therapeutic approaches to AD based on the clearing of amyloid plaques have failed [16], and we are looking for alternative strategies targeting neurotoxic oligomers for both AD and PD [17,18,19,20,21]

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