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Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease

Yaping Chu, Warren D. Hirst, Howard J. Federoff, Ashley S. Harms, A. Jon Stoessl, Jeffrey H. Kordower
doi: https://doi.org/10.1101/2022.08.04.502831
Yaping Chu
1ASU-Banner Neurodegenerative Disease Research Center, Arizona State University 797 East Tyler, Tempe, AZ85281, USA
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Warren D. Hirst
2Neurodegenerative Diseases Research Unit, Biogen, 115 Broadway, Cambridge, MA 02142, USA
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Howard J. Federoff
3Neurology, School of Medicine, Georgetown University Medical Center, DC 20007, USA
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Ashley S. Harms
4Department of Neurology, University of Alabama at Birmingham, AL 35294, USA
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A. Jon Stoessl
5Department of Neurology, University of British Columbia BC, Canada
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Jeffrey H. Kordower
1ASU-Banner Neurodegenerative Disease Research Center, Arizona State University 797 East Tyler, Tempe, AZ85281, USA
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  • For correspondence: jeffrey.kordower@asu.edu
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Abstract

While Parkinson’s disease (PD) remains clinically defined by cardinal motor symptoms resulting from nigrostriatal degeneration, it is now appreciated that PD consists of multiple pathologies, but it is unclear which occurs first and which are responsible for the nigrostriatal degeneration. For the past number of years, we have been studying a well-characterized cohort of subjects with motor impairment that we have termed mild motor deficits (MMD). Motor deficits were determined on a modified and validated Unified Parkinson’s Disease Rating Scale III (UPDRS III), but they occur to a degree insufficient to diagnose PD. We consider this population to have prodromal PD. However, in past studies, cases in this cohort had a selection bias as both a clinical syndrome in between no motor deficits and PD, plus nigral Lewy pathology as defined post-mortem, were required for inclusion. Therefore, in this study, we only based inclusion on a clinical phenotype intermediate between no motor impairment and PD. Then, we divided this group further based upon whether or not they had a synucleinopathy. Here we demonstrate that loss of nigral dopaminergic neurons, loss of putamenal dopaminergic innervation, loss of TH-phenotype in the substantia nigra and putamen, and changes in axonal transport occur equally in groups with and without nigral alpha-synuclein aggregates. Indeed, the common feature of these two groups is that both have similar degrees of AT8-expressing phospho-tau, a pathology not seen in the nigrostriatal system of aged-matched controls. These finding were confirmed with early (CP13) and late (PHF1) tau markers. This suggests that the initiation of nigrostriatal dopaminergic neurodegeneration occurs independently of alpha-synuclein aggregation and is likely tau mediated.

Competing Interest Statement

The authors have declared no competing interest.

  • Abbreviations

    PD
    Parkinson’s disease;
    AT8
    phosphor-Ser202+Thr205;
    p-S129
    phosphor-S129 α-synuclein;
    TH
    tyrosine hydroxylase;
    NM
    neuromelanin;
    ir
    immunoreactive;
    α-syn
    alpha-synuclein.
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    Posted August 06, 2022.
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    Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease
    Yaping Chu, Warren D. Hirst, Howard J. Federoff, Ashley S. Harms, A. Jon Stoessl, Jeffrey H. Kordower
    bioRxiv 2022.08.04.502831; doi: https://doi.org/10.1101/2022.08.04.502831
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    Is Tau the Initial Pathology in Dopaminergic Nigrostriatal Degeneration? Studies in Parkinsonism and Parkinson’s Disease
    Yaping Chu, Warren D. Hirst, Howard J. Federoff, Ashley S. Harms, A. Jon Stoessl, Jeffrey H. Kordower
    bioRxiv 2022.08.04.502831; doi: https://doi.org/10.1101/2022.08.04.502831

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