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Lewy body extracts from Parkinson disease brains trigger α-synuclein pathology and neurodegeneration in mice and monkeys

Authors

  • Ariadna Recasens PhD,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain
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  • Benjamin Dehay PhD,

    1. Institute of Neurodegenerative Diseases, University of Bordeaux, Bordeaux, France
    2. Institute of Neurodegenerative Diseases, National Center for Scientific Research, Bordeaux, France
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  • Jordi Bové PhD,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain
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  • Iria Carballo-Carbajal PhD,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain
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  • Sandra Dovero,

    1. Institute of Neurodegenerative Diseases, University of Bordeaux, Bordeaux, France
    2. Institute of Neurodegenerative Diseases, National Center for Scientific Research, Bordeaux, France
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  • Ana Pérez-Villalba PhD,

    1. Department of Cell Biology-Center for Networked Biomedical Research on Neurodegenerative Diseases, University of Valencia, Valencia, Spain
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  • Pierre-Olivier Fernagut PhD,

    1. Institute of Neurodegenerative Diseases, University of Bordeaux, Bordeaux, France
    2. Institute of Neurodegenerative Diseases, National Center for Scientific Research, Bordeaux, France
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  • Javier Blesa PhD,

    1. Basal Ganglia and Movement Disorders Unit, Center for Applied Medical Research, University of Navarra-Center for Networked Biomedical Research on Neurodegenerative Diseases, Pamplona, Spain
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  • Annabelle Parent,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain
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  • Celine Perier PhD,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain
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  • Isabel Fariñas PhD,

    1. Department of Cell Biology-Center for Networked Biomedical Research on Neurodegenerative Diseases, University of Valencia, Valencia, Spain
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  • José A. Obeso MD, PhD,

    1. Basal Ganglia and Movement Disorders Unit, Center for Applied Medical Research, University of Navarra-Center for Networked Biomedical Research on Neurodegenerative Diseases, Pamplona, Spain
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  • Erwan Bezard PhD,

    Corresponding author
    1. Institute of Neurodegenerative Diseases, University of Bordeaux, Bordeaux, France
    2. Institute of Neurodegenerative Diseases, National Center for Scientific Research, Bordeaux, France
    • Address correspondence to Dr Vila, Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain. E-mail: mvila@ir.vhebron.net and to Dr Bezard, Institute of Neurodegenerative Diseases, University of Bordeaux, Bordeaux, France. E-mail: erwan.bezard@u-bordeaux2.fr

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  • Miquel Vila MD, PhD

    Corresponding author
    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases, Barcelona, Spain
    2. Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain
    3. Catalan Institution for Research and Advanced Studies, Barcelona, Spain
    • Address correspondence to Dr Vila, Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute–Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Barcelona, Spain. E-mail: mvila@ir.vhebron.net and to Dr Bezard, Institute of Neurodegenerative Diseases, University of Bordeaux, Bordeaux, France. E-mail: erwan.bezard@u-bordeaux2.fr

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Abstract

Objective

Mounting evidence suggests that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans.

Methods

Nigral LB-enriched fractions containing pathological α-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue.

Results

In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein.

Interpretation

α-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration. ANN NEUROL 2014;75:351–362

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