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α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization

Synucleinopathies form a group of neurodegenerative diseases defined by the misfolding and aggregation of α-synuclein (α-syn). Abnormal accumulation and spreading of α-syn aggregates lead to synapse dysfunction and neuronal cell death. Yet, little is known about the synaptic mechanisms underlying th...

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Autores principales: Feller, Benjamin, Fallon, Aurélie, Luo, Wen, Nguyen, Phuong Trang, Shlaifer, Irina, Lee, Alfred Kihoon, Chofflet, Nicolas, Yi, Nayoung, Khaled, Husam, Karkout, Samer, Bourgault, Steve, Durcan, Thomas M., Takahashi, Hideto
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093570/
https://www.ncbi.nlm.nih.gov/pubmed/37048156
http://dx.doi.org/10.3390/cells12071083
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author Feller, Benjamin
Fallon, Aurélie
Luo, Wen
Nguyen, Phuong Trang
Shlaifer, Irina
Lee, Alfred Kihoon
Chofflet, Nicolas
Yi, Nayoung
Khaled, Husam
Karkout, Samer
Bourgault, Steve
Durcan, Thomas M.
Takahashi, Hideto
author_facet Feller, Benjamin
Fallon, Aurélie
Luo, Wen
Nguyen, Phuong Trang
Shlaifer, Irina
Lee, Alfred Kihoon
Chofflet, Nicolas
Yi, Nayoung
Khaled, Husam
Karkout, Samer
Bourgault, Steve
Durcan, Thomas M.
Takahashi, Hideto
author_sort Feller, Benjamin
collection PubMed
description Synucleinopathies form a group of neurodegenerative diseases defined by the misfolding and aggregation of α-synuclein (α-syn). Abnormal accumulation and spreading of α-syn aggregates lead to synapse dysfunction and neuronal cell death. Yet, little is known about the synaptic mechanisms underlying the α-syn pathology. Here we identified β-isoforms of neurexins (β-NRXs) as presynaptic organizing proteins that interact with α-syn preformed fibrils (α-syn PFFs), toxic α-syn aggregates, but not α-syn monomers. Our cell surface protein binding assays and surface plasmon resonance assays reveal that α-syn PFFs bind directly to β-NRXs through their N-terminal histidine-rich domain (HRD) at the nanomolar range (K(D): ~500 nM monomer equivalent). Furthermore, our artificial synapse formation assays show that α-syn PFFs diminish excitatory and inhibitory presynaptic organization induced by a specific isoform of neuroligin 1 that binds only β-NRXs, but not α-isoforms of neurexins. Thus, our data suggest that α-syn PFFs interact with β-NRXs to inhibit β-NRX-mediated presynaptic organization, providing novel molecular insight into how α-syn PFFs induce synaptic pathology in synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies.
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spelling pubmed-100935702023-04-13 α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization Feller, Benjamin Fallon, Aurélie Luo, Wen Nguyen, Phuong Trang Shlaifer, Irina Lee, Alfred Kihoon Chofflet, Nicolas Yi, Nayoung Khaled, Husam Karkout, Samer Bourgault, Steve Durcan, Thomas M. Takahashi, Hideto Cells Article Synucleinopathies form a group of neurodegenerative diseases defined by the misfolding and aggregation of α-synuclein (α-syn). Abnormal accumulation and spreading of α-syn aggregates lead to synapse dysfunction and neuronal cell death. Yet, little is known about the synaptic mechanisms underlying the α-syn pathology. Here we identified β-isoforms of neurexins (β-NRXs) as presynaptic organizing proteins that interact with α-syn preformed fibrils (α-syn PFFs), toxic α-syn aggregates, but not α-syn monomers. Our cell surface protein binding assays and surface plasmon resonance assays reveal that α-syn PFFs bind directly to β-NRXs through their N-terminal histidine-rich domain (HRD) at the nanomolar range (K(D): ~500 nM monomer equivalent). Furthermore, our artificial synapse formation assays show that α-syn PFFs diminish excitatory and inhibitory presynaptic organization induced by a specific isoform of neuroligin 1 that binds only β-NRXs, but not α-isoforms of neurexins. Thus, our data suggest that α-syn PFFs interact with β-NRXs to inhibit β-NRX-mediated presynaptic organization, providing novel molecular insight into how α-syn PFFs induce synaptic pathology in synucleinopathies such as Parkinson’s disease and dementia with Lewy bodies. MDPI 2023-04-04 /pmc/articles/PMC10093570/ /pubmed/37048156 http://dx.doi.org/10.3390/cells12071083 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Feller, Benjamin
Fallon, Aurélie
Luo, Wen
Nguyen, Phuong Trang
Shlaifer, Irina
Lee, Alfred Kihoon
Chofflet, Nicolas
Yi, Nayoung
Khaled, Husam
Karkout, Samer
Bourgault, Steve
Durcan, Thomas M.
Takahashi, Hideto
α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization
title α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization
title_full α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization
title_fullStr α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization
title_full_unstemmed α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization
title_short α-Synuclein Preformed Fibrils Bind to β-Neurexins and Impair β-Neurexin-Mediated Presynaptic Organization
title_sort α-synuclein preformed fibrils bind to β-neurexins and impair β-neurexin-mediated presynaptic organization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093570/
https://www.ncbi.nlm.nih.gov/pubmed/37048156
http://dx.doi.org/10.3390/cells12071083
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