Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers
The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors fo...
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doaj-03241811a4b9437d8aa33d3e64f302082020-11-25T04:06:01ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-11-01218535853510.3390/ijms21228535Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein OligomersLaura Boi0Augusta Pisanu1Maria Francesca Palmas2Giuliana Fusco3Ezio Carboni4Maria Antonietta Casu5Valentina Satta6Maria Scherma7Elzbieta Janda8Ignazia Mocci9Giovanna Mulas10Anna Ena11Saturnino Spiga12Paola Fadda13Alfonso De Simone14Anna R. Carta15Department of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyCNR Institute of Neuroscience, 09042 Cagliari, ItalyDepartment of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyCentre for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UKDepartment of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyCNR Institute of Translational Pharmacology, 09010 Cagliari, ItalyDepartment of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyDepartment of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyDepartment of Health Sciences, Magna Graecia University, 88100 Catanzaro, ItalyCNR Institute of Translational Pharmacology, 09010 Cagliari, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, 09126 Cagliari, ItalyDepartment of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyDepartment of Life and Environmental Sciences, University of Cagliari, 09126 Cagliari, ItalyDepartment of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyDepartment of Life Sciences, Imperial College London, London SW7 2AZ, UKDepartment of Biomedical Sciences, University of Cagliari, 09042 Cagliari, ItalyThe accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies.https://www.mdpi.com/1422-0067/21/22/8535Parkinson diseaseα-synuclein oligomersneurodegenerationneuroinflammationmicrogliamotor deficits |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Laura Boi Augusta Pisanu Maria Francesca Palmas Giuliana Fusco Ezio Carboni Maria Antonietta Casu Valentina Satta Maria Scherma Elzbieta Janda Ignazia Mocci Giovanna Mulas Anna Ena Saturnino Spiga Paola Fadda Alfonso De Simone Anna R. Carta |
spellingShingle |
Laura Boi Augusta Pisanu Maria Francesca Palmas Giuliana Fusco Ezio Carboni Maria Antonietta Casu Valentina Satta Maria Scherma Elzbieta Janda Ignazia Mocci Giovanna Mulas Anna Ena Saturnino Spiga Paola Fadda Alfonso De Simone Anna R. Carta Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers International Journal of Molecular Sciences Parkinson disease α-synuclein oligomers neurodegeneration neuroinflammation microglia motor deficits |
author_facet |
Laura Boi Augusta Pisanu Maria Francesca Palmas Giuliana Fusco Ezio Carboni Maria Antonietta Casu Valentina Satta Maria Scherma Elzbieta Janda Ignazia Mocci Giovanna Mulas Anna Ena Saturnino Spiga Paola Fadda Alfonso De Simone Anna R. Carta |
author_sort |
Laura Boi |
title |
Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers |
title_short |
Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers |
title_full |
Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers |
title_fullStr |
Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers |
title_full_unstemmed |
Modeling Parkinson’s Disease Neuropathology and Symptoms by Intranigral Inoculation of Preformed Human α-Synuclein Oligomers |
title_sort |
modeling parkinson’s disease neuropathology and symptoms by intranigral inoculation of preformed human α-synuclein oligomers |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-11-01 |
description |
The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies. |
topic |
Parkinson disease α-synuclein oligomers neurodegeneration neuroinflammation microglia motor deficits |
url |
https://www.mdpi.com/1422-0067/21/22/8535 |
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