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DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease

Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), wh...

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Autores principales: Masato, Anna, Plotegher, Nicoletta, Terrin, Francesca, Sandre, Michele, Faustini, Gaia, Thor, Andrea, Adams, Stephen, Berti, Giulia, Cogo, Susanna, De Lazzari, Federica, Fontana, Camilla Maria, Martinez, Paul Anthony, Strong, Randy, Bandopadhyay, Rina, Bisaglia, Marco, Bellucci, Arianna, Greggio, Elisa, Dalla Valle, Luisa, Boassa, Daniela, Bubacco, Luigi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039907/
https://www.ncbi.nlm.nih.gov/pubmed/36966140
http://dx.doi.org/10.1038/s41531-023-00485-1
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author Masato, Anna
Plotegher, Nicoletta
Terrin, Francesca
Sandre, Michele
Faustini, Gaia
Thor, Andrea
Adams, Stephen
Berti, Giulia
Cogo, Susanna
De Lazzari, Federica
Fontana, Camilla Maria
Martinez, Paul Anthony
Strong, Randy
Bandopadhyay, Rina
Bisaglia, Marco
Bellucci, Arianna
Greggio, Elisa
Dalla Valle, Luisa
Boassa, Daniela
Bubacco, Luigi
author_facet Masato, Anna
Plotegher, Nicoletta
Terrin, Francesca
Sandre, Michele
Faustini, Gaia
Thor, Andrea
Adams, Stephen
Berti, Giulia
Cogo, Susanna
De Lazzari, Federica
Fontana, Camilla Maria
Martinez, Paul Anthony
Strong, Randy
Bandopadhyay, Rina
Bisaglia, Marco
Bellucci, Arianna
Greggio, Elisa
Dalla Valle, Luisa
Boassa, Daniela
Bubacco, Luigi
author_sort Masato, Anna
collection PubMed
description Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration.
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spelling pubmed-100399072023-03-27 DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease Masato, Anna Plotegher, Nicoletta Terrin, Francesca Sandre, Michele Faustini, Gaia Thor, Andrea Adams, Stephen Berti, Giulia Cogo, Susanna De Lazzari, Federica Fontana, Camilla Maria Martinez, Paul Anthony Strong, Randy Bandopadhyay, Rina Bisaglia, Marco Bellucci, Arianna Greggio, Elisa Dalla Valle, Luisa Boassa, Daniela Bubacco, Luigi NPJ Parkinsons Dis Article Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration. Nature Publishing Group UK 2023-03-25 /pmc/articles/PMC10039907/ /pubmed/36966140 http://dx.doi.org/10.1038/s41531-023-00485-1 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Masato, Anna
Plotegher, Nicoletta
Terrin, Francesca
Sandre, Michele
Faustini, Gaia
Thor, Andrea
Adams, Stephen
Berti, Giulia
Cogo, Susanna
De Lazzari, Federica
Fontana, Camilla Maria
Martinez, Paul Anthony
Strong, Randy
Bandopadhyay, Rina
Bisaglia, Marco
Bellucci, Arianna
Greggio, Elisa
Dalla Valle, Luisa
Boassa, Daniela
Bubacco, Luigi
DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease
title DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease
title_full DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease
title_fullStr DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease
title_full_unstemmed DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease
title_short DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease
title_sort dopal initiates αsynuclein-dependent impaired proteostasis and degeneration of neuronal projections in parkinson’s disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10039907/
https://www.ncbi.nlm.nih.gov/pubmed/36966140
http://dx.doi.org/10.1038/s41531-023-00485-1
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