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α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss

AIMS: We previously found that a decoy peptide derived from the C‐terminal sequence of α‐Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid‐binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn‐derived peptides to further validate their effects on αSy...

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Autores principales: Guo, Qingyun, Kawahata, Ichiro, Jia, Wenbin, Wang, Haoyang, Cheng, An, Yabuki, Yasushi, Shioda, Norifumi, Fukunaga, Kohji
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173724/
https://www.ncbi.nlm.nih.gov/pubmed/36786129
http://dx.doi.org/10.1111/cns.14120
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author Guo, Qingyun
Kawahata, Ichiro
Jia, Wenbin
Wang, Haoyang
Cheng, An
Yabuki, Yasushi
Shioda, Norifumi
Fukunaga, Kohji
author_facet Guo, Qingyun
Kawahata, Ichiro
Jia, Wenbin
Wang, Haoyang
Cheng, An
Yabuki, Yasushi
Shioda, Norifumi
Fukunaga, Kohji
author_sort Guo, Qingyun
collection PubMed
description AIMS: We previously found that a decoy peptide derived from the C‐terminal sequence of α‐Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid‐binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn‐derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)‐injected mouse model of Parkinson's disease (PD). METHODS: Mice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2‐week intervals post‐injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co‐immunoprecipitation. RESULTS: αSyn PFF‐injected mice showed significant memory loss but no motor function impairment. Long‐term nasal treatment with peptides effectively prevented memory impairment. In peptide‐treated αSyn PFF‐injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn‐FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3. CONCLUSIONS: Our findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn‐FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies.
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spelling pubmed-101737242023-05-12 α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss Guo, Qingyun Kawahata, Ichiro Jia, Wenbin Wang, Haoyang Cheng, An Yabuki, Yasushi Shioda, Norifumi Fukunaga, Kohji CNS Neurosci Ther Original Articles AIMS: We previously found that a decoy peptide derived from the C‐terminal sequence of α‐Synuclein (αSyn) prevents cytotoxic αSyn aggregation caused by fatty acid‐binding protein 3 (FABP3) in vitro. In this study, we continued to utilize αSyn‐derived peptides to further validate their effects on αSyn neurotoxicity and behavioral impairments in αSyn preformed fibrils (PFFs)‐injected mouse model of Parkinson's disease (PD). METHODS: Mice were injected with αSyn PFFs in the bilateral olfactory bulb (OB) and then were subjected to behavioral analysis at 2‐week intervals post‐injection. Peptides nasal administration was initiated one week after injection. Changes in phosphorylation of αSyn and neuronal damage in the OB were measured using immunostaining at week 4. The effect of peptides on the interaction between αSyn and FABP3 was examined using co‐immunoprecipitation. RESULTS: αSyn PFF‐injected mice showed significant memory loss but no motor function impairment. Long‐term nasal treatment with peptides effectively prevented memory impairment. In peptide‐treated αSyn PFF‐injected mice, the peptides entered the OB smoothly through the nasal cavity and were mainly concentrated in neurons in the mitral cell layer, significantly suppressing the excessive phosphorylation of αSyn and reducing the formation of αSyn‐FABP3 oligomers, thereby preventing neuronal death. The addition of peptides also blocked the interaction of αSyn and FABP3 at the recombinant protein level, and its effect was strongest at molar concentrations comparable to those of αSyn and FABP3. CONCLUSIONS: Our findings suggest that the αSyn decoy peptide represents a novel therapeutic approach for reducing the accumulation of toxic αSyn‐FABP3 oligomers in the brain, thereby preventing the progression of synucleinopathies. John Wiley and Sons Inc. 2023-02-14 /pmc/articles/PMC10173724/ /pubmed/36786129 http://dx.doi.org/10.1111/cns.14120 Text en © 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Guo, Qingyun
Kawahata, Ichiro
Jia, Wenbin
Wang, Haoyang
Cheng, An
Yabuki, Yasushi
Shioda, Norifumi
Fukunaga, Kohji
α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss
title α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss
title_full α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss
title_fullStr α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss
title_full_unstemmed α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss
title_short α‐Synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss
title_sort α‐synuclein decoy peptide protects mice against α‐synuclein‐induced memory loss
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10173724/
https://www.ncbi.nlm.nih.gov/pubmed/36786129
http://dx.doi.org/10.1111/cns.14120
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