DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson’s disease Article Swipe

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Anna Masato , Nicoletta Plotegher , Andrea Thor , Stephen Adams , Michele Sandre , Susanna Cogo , Federica De Lazzari , Camilla Maria Fontana , Paul Anthony Martinez , Randy Strong , Arianna Bellucci , Marco Bisaglia , Elisa Greggio , Luisa Dalla Valle , Daniela Boassa , Luigi Bubacco ·

YOU? · · 2021 · Open Access · · DOI: https://doi.org/10.1101/2021.06.15.448476

Dopamine dyshomeostasis has been acknowledged to be 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 aldehydic 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 neuronal accumulation and hampers αSyn clearance at synapses and the soma. By combining cellular and in vivo models, we provided evidence that DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways, specifically at neuronal projections. The resulting progressive decline of neuronal homeostasis leads to dopaminergic neuron loss and motor impairment, corroborating the αSyn-DOPAL interplay as an early event in PD neurodegeneration.

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Neuroscience Neurodegeneration Dopaminergic Proteostasis Dopamine Parkinson's disease Synucleinopathies Biology Alpha-synuclein Chemistry Disease Cell biology Medicine Internal medicine

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Type: preprint
Language: en
Landing Page: https://doi.org/10.1101/2021.06.15.448476
PDF: https://www.biorxiv.org/content/biorxiv/early/2021/06/16/2021.06.15.448476.full.pdf
OA Status: green
Cited By: 2
References: 67
Related Works: 10
OpenAlex ID: https://openalex.org/W3171423299

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DOI: https://doi.org/10.1101/2021.06.15.448476

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Title: DOPAL initiates αSynuclein-mediated impaired proteostasis in neuronal projections leading to enhanced vulnerability in Parkinson’s disease

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Type: preprint

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Language: en

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Publication year: 2021

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Publication date: 2021-06-16

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Authors: Anna Masato, Nicoletta Plotegher, Andrea Thor, Stephen Adams, Michele Sandre, Susanna Cogo, Federica De Lazzari, Camilla Maria Fontana, Paul Anthony Martinez, Randy Strong, Arianna Bellucci, Marco Bisaglia, Elisa Greggio, Luisa Dalla Valle, Daniela Boassa, Luigi Bubacco

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Landing page: https://doi.org/10.1101/2021.06.15.448476

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PDF URL: https://www.biorxiv.org/content/biorxiv/early/2021/06/16/2021.06.15.448476.full.pdf

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Concepts: Neuroscience, Neurodegeneration, Dopaminergic, Proteostasis, Dopamine, Parkinson's disease, Synucleinopathies, Biology, Alpha-synuclein, Chemistry, Disease, Cell biology, Medicine, Internal medicine

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Cited by: 2

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