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Neuronal hemoglobin induces α-synuclein cleavage and loss of dopaminergic neurons

Santulli Chiara, Bon Carlotta, De Cecco Elena, Codrich Marta, Narkiewicz Joanna, Parisse Pietro, Perissinotto Fabio, Claudio Santoro, Francesca Persichetti, Legname Giuseppe, Stefano Espinoza, Gustincich Stefano
doi: https://doi.org/10.1101/2021.10.13.464204
Santulli Chiara
1Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
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Bon Carlotta
2Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy
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De Cecco Elena
1Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
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Codrich Marta
1Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
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Narkiewicz Joanna
1Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
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Parisse Pietro
3ELETTRA Synchrotron Light Source, Trieste, Italy
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Perissinotto Fabio
3ELETTRA Synchrotron Light Source, Trieste, Italy
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Claudio Santoro
4Department of Health Sciences and Research Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
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Francesca Persichetti
4Department of Health Sciences and Research Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
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Legname Giuseppe
1Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
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Stefano Espinoza
2Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy
4Department of Health Sciences and Research Center on Autoimmune and Allergic Diseases (CAAD), University of Piemonte Orientale (UPO), Novara, Italy
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  • For correspondence: stefano.gustincich@iit.it stefano.espinoza@iit.it
Gustincich Stefano
1Area of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
2Central RNA Laboratory, Istituto Italiano di Tecnologia (IIT), Genova, Italy
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  • For correspondence: stefano.gustincich@iit.it stefano.espinoza@iit.it
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ABSTRACT

Backgroud α-synuclein, a protein involved in the pathogenesis of several neurodegenerative disorders, is subjected to several post-translational modifications. Among them, C-terminal truncation seems to increase its aggregation propensity in vitro. Hemoglobin is the major protein in erythrocytes to carries oxygen and recently is found to be expressed in dopaminergic neurons and to be involved in the pathogenesis of neurodegenerative diseases such as Parkinson’s disease.

Methods To assess the role of hemoglobin in α-synuclein post-translational modification and in dopamine cells physiology, we over-expressed α and β-chains of Hb in iMN9D dopamine cells to evaluate its effect on α-synuclein truncation. Using an AAV9 we expressed α and β-chains of hemoglobin in dopamine neurons of Substantia Nigra pars compacta and evaluate its effect on α-synuclein post-translational modification, dopamine neurons survivals and behavioural outcome.

Results The over-expression of α and β-chains of hemoglobin in iMN9D dopamine cells increased C-terminal truncation of α-synuclein when cells were treated with α-synuclein preformed fibrils. This cleavage was led at least in part by Calpain protease. Hemoglobin over-expression in Substantia Nigra pars compacta induced a similar pattern of α-synuclein truncation and a decrease in tyrosine hydroxylase expression, unveiling a decrease of dopamine neurons of about 50%. This dopamine cells loss led to a mild motor impairment and a deficit in recognition and spatial working memory.

Conclusion Our study reveals a novel role for hemoglobin in α-synuclein post-translational modification and in dopamine neurons homeostasis suggesting neuronal hemoglobin is an important modifier in synucleinopathies such as Parkinson’s disease.

Competing Interest Statement

The authors have declared no competing interest.

  • ABBREVIATIONS

    α-syn
    alpha-synuclein
    Ms
    monomers
    PTMs
    post-translational modifications
    pSer-129
    phosphorylated serine 129
    ΔC- α-syn
    C-terminal truncated α-syn
    FL- α-syn
    full-length α-syn
    PD
    Parkinson’s disease
    LBD
    Lewy Body Dementia
    MSA
    Multiple System Atrophy
    SNpc
    Subtantia nigra pars compacta
    GCIs
    Glial cytoplasmic inclusions
    DA
    dopaminergic
    Hb
    hemoglobin
    nHb
    neuronal Hb
    MPP+
    1-methyl-4-phenylpyridinium
    PFFs
    pre-formed fibrils
    AFM
    Atomic force microscopy
    NHP
    non-human primates
    Capn I
    Calpain I
    Ctsd
    cathepsin D
    Cas1
    caspase 1
    TH
    tyrosine hydroxylase
    NOR
    novel object recognition;
  • Copyright 
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    Posted October 14, 2021.
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    Neuronal hemoglobin induces α-synuclein cleavage and loss of dopaminergic neurons
    Santulli Chiara, Bon Carlotta, De Cecco Elena, Codrich Marta, Narkiewicz Joanna, Parisse Pietro, Perissinotto Fabio, Claudio Santoro, Francesca Persichetti, Legname Giuseppe, Stefano Espinoza, Gustincich Stefano
    bioRxiv 2021.10.13.464204; doi: https://doi.org/10.1101/2021.10.13.464204
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    Neuronal hemoglobin induces α-synuclein cleavage and loss of dopaminergic neurons
    Santulli Chiara, Bon Carlotta, De Cecco Elena, Codrich Marta, Narkiewicz Joanna, Parisse Pietro, Perissinotto Fabio, Claudio Santoro, Francesca Persichetti, Legname Giuseppe, Stefano Espinoza, Gustincich Stefano
    bioRxiv 2021.10.13.464204; doi: https://doi.org/10.1101/2021.10.13.464204

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