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

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.

The Epigenetic Dimension of Protein Structure Is an Intrinsic Weakness of the AlphaFold Program

“…However, it excludes common post-translational modifications of proteins, such as phosphorylation, glycosylation or lipidation, that can be predicted from consensus amino acid motifs [ 3 ]. Membrane proteins are a perfect example of this paradigm, as specific lipids act as key cofactors (i.e., chaperones) for protein folding and stability [ 27 , 38 , 39 , 40 , 41 , 42 ]. The existence of protein-lipid “co-structures” have been identified as an issue for the heterologous expression of membrane proteins [ 43 ].…”

Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

“…Such pores can allow a catastrophic and irreversible entry of calcium ions [87]. This has led to the construction of a small peptide inhibitor that recognizes the gangliosides that are implicated in the initial binding step of amyloid proteins to the lipid rafts of the cell membranes, thereby blocking the neurodegeneration-provoking calcium influx [88,89].…”

Gangliosides as Biomarkers of Human Brain Diseases: Trends in Discovery and Characterization by High-Performance Mass Spectrometry

“…Among such oligomers, those forming pores in the plasma membrane of brain cells exhibit the highest toxicity since such species favor the penetration of Ca 2+ ions in massive amounts. The investigation of GG involvement in the toxicity of these oligomers has recently confirmed that gangliosides are relevant therapeutic targets for both AD and PD [ 82 ]. On the other hand, the ability of GM1 to protect against α-synuclein toxicity in vivo has also been postulated.…”