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14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model

Rachel Underwood, Mary Gannon, Aneesh Pathak, Navya Kapa, Sidhanth Chandra, Alyssa Klop, View ORCID ProfileTalene A. Yacoubian
doi: https://doi.org/10.1101/2020.11.17.387415
Rachel Underwood
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Mary Gannon
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Aneesh Pathak
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Navya Kapa
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Sidhanth Chandra
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Alyssa Klop
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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Talene A. Yacoubian
Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294
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  • ORCID record for Talene A. Yacoubian
  • For correspondence: tyacoubian@uabmc.edu
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Abstract

Alpha-synuclein (αsyn) is the key component of proteinaceous aggregates termed Lewy Bodies (LBs) that pathologically define a group of disorders known as synucleinopathies, including Parkinson’s Disease (PD) and Dementia with Lewy Bodies (DLB). αSyn is hypothesized to misfold and spread throughout the brain in a prion-like fashion. Transmission of αsyn necessitates the release of misfolded αsyn from one cell and the uptake of that αsyn by another, in which it can template the misfolding of endogenous αsyn upon cell internalization. 14-3-3 proteins are a family of highly expressed brain proteins that are neuroprotective in multiple PD models. We have previously shown that 14-3-3θ acts as a chaperone to reduce αsyn aggregation, cell-to-cell transmission, and neurotoxicity in the in vitro pre-formed fibril (PFF) model. In this study, we expanded our studies to test the impact of 14-3-3s on αsyn toxicity in the in vivo αsyn PFF model. We used both transgenic expression models and adenovirus associated virus (AAV)-mediated expression to examine whether 14-3-3 manipulation impacts behavioral deficits, αsyn aggregation, and neuronal loss in the PFF model. 14-3-3θ transgene overexpression in cortical and amygdala regions rescued social dominance deficits induced by PFFs at 6 months post injection, whereas 14-3-3 inhibition by transgene expression of the competitive 14-3-3 peptide inhibitor difopein in the cortex and amygdala accelerated social dominance deficits. The behavioral rescue by 14-3-3θ overexpression was associated with delayed αsyn aggregation induced by PFFs in these brain regions. Conversely, 14-3-3 inhibition by difopein in the cortex and amygdala accelerated αsyn aggregation and cortical pyramidal neuron loss induced by PFFs. 14-3-3θ overexpression by AAV in the substantia nigra (SN) also delayed αsyn aggregation in the SN and partially rescued PFF-induced dopaminergic cell loss in the SN. 14-3-3 inhibition in the SN accelerated nigral αsyn aggregation and increased PFF-induced dopaminergic cell loss. These data indicate a neuroprotective role for 14-3-3θ against αsyn toxicity in vivo.

Competing Interest Statement

Dr. Yacoubian has a U.S. Patent No. 7,919,262 on the use of 14-3-3s in neurodegeneration. The remaining authors have no competing interests to declare.

  • List of abbreviations:

    AAV
    adenovirus associated virus
    αsyn
    alpha-synuclein
    CTX
    cortex
    DLB
    Dementia with Lewy Bodies
    IHC
    immunohistochemistry
    LB
    Lewy body
    mpi
    months post injection
    PD
    Parkinson’s disease
    PFF
    pre-formed fibrils
    pS129-
    phosphoserine 129
    SN
    substantia nigra
    TH
    tyrosine hydroxylase
  • Copyright 
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    14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model
    Rachel Underwood, Mary Gannon, Aneesh Pathak, Navya Kapa, Sidhanth Chandra, Alyssa Klop, Talene A. Yacoubian
    bioRxiv 2020.11.17.387415; doi: https://doi.org/10.1101/2020.11.17.387415
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    14-3-3 mitigates alpha-synuclein aggregation and toxicity in the in vivo preformed fibril model
    Rachel Underwood, Mary Gannon, Aneesh Pathak, Navya Kapa, Sidhanth Chandra, Alyssa Klop, Talene A. Yacoubian
    bioRxiv 2020.11.17.387415; doi: https://doi.org/10.1101/2020.11.17.387415

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