Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis
Abstract Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and...
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doaj-943a61fb6416419f8a5f2b309df54f802021-01-17T12:04:58ZengNature Publishing GroupCell Death and Disease2041-48892021-01-0112111410.1038/s41419-020-03369-xIntranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularisJian-Jun Guo0Feng Yue1Dong-Yan Song2Luc Bousset3Xin Liang4Jing Tang5Lin Yuan6Wen Li7Ronald Melki8Yong Tang9Piu Chan10Chuang Guo11Jia-Yi Li12Institute of Neuroscience, College of Life and Health Sciences, Northeastern UniversityBeijing Key Laboratory of Parkinson’s Disease, National Clinical Research Center for Geriatric Disorders, Department of Neurobiology, Xuanwu Hospital of Capital Medical UniversityInstitute of Neuroscience, College of Life and Health Sciences, Northeastern UniversityLaboratory of Neurodegenerative Diseases, CNRS and Institut François Jacob (MIRCen), CEADepartment of Histology, Chongqing Medical UniversityDepartment of Histology, Chongqing Medical UniversityUnit of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical UniversityUnit of Neurodegenerative Diseases and Repair, Institute of Health Sciences, China Medical UniversityLaboratory of Neurodegenerative Diseases, CNRS and Institut François Jacob (MIRCen), CEADepartment of Histology, Chongqing Medical UniversityBeijing Key Laboratory of Parkinson’s Disease, National Clinical Research Center for Geriatric Disorders, Department of Neurobiology, Xuanwu Hospital of Capital Medical UniversityInstitute of Neuroscience, College of Life and Health Sciences, Northeastern UniversityInstitute of Neuroscience, College of Life and Health Sciences, Northeastern UniversityAbstract Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD.https://doi.org/10.1038/s41419-020-03369-x |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jian-Jun Guo Feng Yue Dong-Yan Song Luc Bousset Xin Liang Jing Tang Lin Yuan Wen Li Ronald Melki Yong Tang Piu Chan Chuang Guo Jia-Yi Li |
spellingShingle |
Jian-Jun Guo Feng Yue Dong-Yan Song Luc Bousset Xin Liang Jing Tang Lin Yuan Wen Li Ronald Melki Yong Tang Piu Chan Chuang Guo Jia-Yi Li Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis Cell Death and Disease |
author_facet |
Jian-Jun Guo Feng Yue Dong-Yan Song Luc Bousset Xin Liang Jing Tang Lin Yuan Wen Li Ronald Melki Yong Tang Piu Chan Chuang Guo Jia-Yi Li |
author_sort |
Jian-Jun Guo |
title |
Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis |
title_short |
Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis |
title_full |
Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis |
title_fullStr |
Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis |
title_full_unstemmed |
Intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of Macaca fascicularis |
title_sort |
intranasal administration of α-synuclein preformed fibrils triggers microglial iron deposition in the substantia nigra of macaca fascicularis |
publisher |
Nature Publishing Group |
series |
Cell Death and Disease |
issn |
2041-4889 |
publishDate |
2021-01-01 |
description |
Abstract Iron deposition is present in main lesion areas in the brains of patients with Parkinson’s disease (PD) and an abnormal iron content may be associated with dopaminergic neuronal cytotoxicity and degeneration in the substantia nigra of the midbrain. However, the cause of iron deposition and its role in the pathological process of PD are unclear. In the present study, we investigated the effects of the nasal mucosal delivery of synthetic human α-synuclein (α-syn) preformed fibrils (PFFs) on the pathogenesis of PD in Macaca fascicularis. We detected that iron deposition was clearly increased in a time-dependent manner from 1 to 17 months in the substantia nigra and globus pallidus, highly contrasting to other brain regions after treatments with α-syn PFFs. At the cellular level, the iron deposits were specifically localized in microglia but not in dopaminergic neurons, nor in other types of glial cells in the substantia nigra, whereas the expression of transferrin (TF), TF receptor 1 (TFR1), TF receptor 2 (TFR2), and ferroportin (FPn) was increased in dopaminergic neurons. Furthermore, no clear dopaminergic neuron loss was observed in the substantia nigra, but with decreased immunoreactivity of tyrosine hydroxylase (TH) and appearance of axonal swelling in the putamen. The brain region-enriched and cell-type-dependent iron localizations indicate that the intranasal α-syn PFFs treatment-induced iron depositions in microglia in the substantia nigra may appear as an early cellular response that may initiate neuroinflammation in the dopaminergic system before cell death occurs. Our data suggest that the inhibition of iron deposition may be a potential approach for the early prevention and treatment of PD. |
url |
https://doi.org/10.1038/s41419-020-03369-x |
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