Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain
Abstract Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-09-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-023-00579-w |
| _version_ | 1827723902765236224 |
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| author | Margaux Teil Sandra Dovero Mathieu Bourdenx Marie-Laure Arotcarena Morgane Darricau Gregory Porras Marie-Laure Thiolat Inés Trigo-Damas Celine Perier Cristina Estrada Nuria Garcia-Carrillo María Trinidad Herrero Miquel Vila José A. Obeso Erwan Bezard Benjamin Dehay |
| author_facet | Margaux Teil Sandra Dovero Mathieu Bourdenx Marie-Laure Arotcarena Morgane Darricau Gregory Porras Marie-Laure Thiolat Inés Trigo-Damas Celine Perier Cristina Estrada Nuria Garcia-Carrillo María Trinidad Herrero Miquel Vila José A. Obeso Erwan Bezard Benjamin Dehay |
| author_sort | Margaux Teil |
| collection | DOAJ |
| description | Abstract Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections’ putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB. |
| first_indexed | 2024-03-10T22:07:20Z |
| format | Article |
| id | doaj.art-5e7c4632b63d47648748ab58e84b753d |
| institution | Directory Open Access Journal |
| issn | 2373-8057 |
| language | English |
| last_indexed | 2024-03-10T22:07:20Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj.art-5e7c4632b63d47648748ab58e84b753d2023-11-19T12:45:48ZengNature Portfolionpj Parkinson's Disease2373-80572023-09-019111310.1038/s41531-023-00579-wCortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brainMargaux Teil0Sandra Dovero1Mathieu Bourdenx2Marie-Laure Arotcarena3Morgane Darricau4Gregory Porras5Marie-Laure Thiolat6Inés Trigo-Damas7Celine Perier8Cristina Estrada9Nuria Garcia-Carrillo10María Trinidad Herrero11Miquel Vila12José A. Obeso13Erwan Bezard14Benjamin Dehay15Univ. Bordeaux, CNRS, IMN, UMR 5293Univ. Bordeaux, CNRS, IMN, UMR 5293Univ. Bordeaux, CNRS, IMN, UMR 5293Univ. Bordeaux, CNRS, IMN, UMR 5293Univ. Bordeaux, CNRS, IMN, UMR 5293Univ. Bordeaux, CNRS, IMN, UMR 5293Univ. Bordeaux, CNRS, IMN, UMR 5293HM CINAC, HM Puerta del Sur, Fundación HM Hospitales and CIBERNED and CEU-San Pablo University MadridCenter for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos IIIClinical and Experimental Neuroscience Unit, School of Medicine, Biomedical Research Institute of Murcia (IMIB), University of Murcia, Campus Mare NostrumCentro Experimental en Investigaciones Biomédica (CEIB), Universidad de MurciaClinical and Experimental Neuroscience Unit, School of Medicine, Biomedical Research Institute of Murcia (IMIB), University of Murcia, Campus Mare NostrumCenter for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Instituto Carlos IIIHM CINAC, HM Puerta del Sur, Fundación HM Hospitales and CIBERNED and CEU-San Pablo University MadridUniv. Bordeaux, CNRS, IMN, UMR 5293Univ. Bordeaux, CNRS, IMN, UMR 5293Abstract Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections’ putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB.https://doi.org/10.1038/s41531-023-00579-w |
| spellingShingle | Margaux Teil Sandra Dovero Mathieu Bourdenx Marie-Laure Arotcarena Morgane Darricau Gregory Porras Marie-Laure Thiolat Inés Trigo-Damas Celine Perier Cristina Estrada Nuria Garcia-Carrillo María Trinidad Herrero Miquel Vila José A. Obeso Erwan Bezard Benjamin Dehay Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain npj Parkinson's Disease |
| title | Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain |
| title_full | Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain |
| title_fullStr | Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain |
| title_full_unstemmed | Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain |
| title_short | Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain |
| title_sort | cortical lewy body injections induce long distance pathogenic alterations in the non human primate brain |
| url | https://doi.org/10.1038/s41531-023-00579-w |
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