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Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration

View ORCID ProfileJessika C. Bridi, View ORCID ProfileErika Bereczki, View ORCID ProfileSaffron K. Smith, View ORCID ProfileGonçalo M. Poças, View ORCID ProfileBenjamin Kottler, View ORCID ProfilePedro M. Domingos, Christopher J. Elliott, View ORCID ProfileDag Aarsland, View ORCID ProfileFrank Hirth
doi: https://doi.org/10.1101/2020.10.12.335778
Jessika C. Bridi
1King’s College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic & Clinical Neuroscience; London, UK
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  • For correspondence: jessikabridi@usp.br Frank.Hirth@kcl.ac.uk
Erika Bereczki
4Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum, Stockholm, Sweden
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Saffron K. Smith
5Department of Biology and York Biomedical Research Institute, University of York, York, YO1 5DD, UK
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Gonçalo M. Poças
3Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Lisbon, Portugal
6School of Biological Sciences, Monash University, Melbourne, Victoria, Australia
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Benjamin Kottler
1King’s College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic & Clinical Neuroscience; London, UK
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Pedro M. Domingos
3Instituto de Tecnologia Química e Biológica António Xavier, Universidade Nova de Lisboa (ITQB NOVA), Oeiras, Lisbon, Portugal
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Christopher J. Elliott
5Department of Biology and York Biomedical Research Institute, University of York, York, YO1 5DD, UK
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Dag Aarsland
2Department of Old Age Psychiatry, Institute of Psychiatry Psychology and Neuroscience, King’s College London, London, UK
4Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Neurogeriatrics, Karolinska Institutet, Novum, Stockholm, Sweden
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Frank Hirth
1King’s College London, Institute of Psychiatry, Psychology & Neuroscience, Maurice Wohl Clinical Neuroscience Institute, Department of Basic & Clinical Neuroscience; London, UK
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  • For correspondence: jessikabridi@usp.br Frank.Hirth@kcl.ac.uk
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Abstract

Alpha-synuclein (α-syn) mislocalisation and accumulation in intracellular inclusions is the major pathological hallmark of degenerative synucleinopathies, including Parkinson’s disease, Parkinson’s disease with Dementia and Dementia with Lewy Bodies. Typical symptoms are behavioural abnormalities including motor deficits that mark disease progression, while non-motor symptoms and synaptic deficits are already apparent during the early stages of disease. Synucleinopathies have therefore been considered synaptopathies that exhibit synaptic dysfunction prior to neurodegeneration. However, the mechanisms and events underlying synaptopathy are largely unknown. Here we investigated the cascade of pathological events underlying α-syn accumulation and toxicity in a Drosophila model of synucleinopathy by employing a combination of histological, biochemical, behavioural and electrophysiological assays. Our findings demonstrate that targeted expression of human α-syn leads to its accumulation in presynaptic terminals that caused downregulation of synaptic proteins, Cysteine String Protein, Synapsin, and Syntaxin 1A, and a reduction in the number of Bruchpilot puncta, the core component of the presynaptic active zone essential for its structural integrity and function. These α-syn-mediated presynaptic alterations resulted in impaired neuronal function, which triggered behavioural deficits in ageing Drosophila that occurred prior to progressive degeneration of dopaminergic neurons. Comparable alterations in presynaptic active zone protein were found in patient brain samples of Dementia with Lewy Bodies. Together, these findings demonstrate that presynaptic accumulation of α-syn impairs the active zone and neuronal function, which together cause synaptopathy that results in behavioural deficits and the progressive loss of dopaminergic neurons. This sequence of events resembles the cytological and behavioural phenotypes that characterise the onset and progression of synucleinopathies, suggesting that α-syn mediated synaptopathy is an initiating cause of age-related neurodegeneration.

Competing Interest Statement

B.K. is co-founder of BFKLab LTD. The remaining authors declare no competing interest.

  • Abbreviations

    AZ
    active zone
    CSP
    Cysteine String Protein
    DA
    dopaminergic
    DART
    Drosophila ARousal Tracking system
    DLB
    Dementia with Lewy bodies
    iSIM
    instant structured illumination microscopy
    NMJ
    neuromuscular junction
    PD
    Parkinson’s disease
    PDD
    Parkinson’s disease Dementia
    PER
    proboscis extension response
    SING
    startled-induced negative geotaxis
    α-syn
    α-synuclein
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    Posted October 12, 2020.
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    Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration
    Jessika C. Bridi, Erika Bereczki, Saffron K. Smith, Gonçalo M. Poças, Benjamin Kottler, Pedro M. Domingos, Christopher J. Elliott, Dag Aarsland, Frank Hirth
    bioRxiv 2020.10.12.335778; doi: https://doi.org/10.1101/2020.10.12.335778
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    Presynaptic accumulation of α-synuclein causes synaptopathy and progressive neurodegeneration
    Jessika C. Bridi, Erika Bereczki, Saffron K. Smith, Gonçalo M. Poças, Benjamin Kottler, Pedro M. Domingos, Christopher J. Elliott, Dag Aarsland, Frank Hirth
    bioRxiv 2020.10.12.335778; doi: https://doi.org/10.1101/2020.10.12.335778

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