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Subcellular Parkinson’s Disease-Specific Alpha-Synuclein Species Show Altered Behavior in Neurodegeneration

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Abstract

Parkinson’s disease and other synucleinopathies are characterized by the presence of intra-neuronal protein aggregates enriched in the presynaptic protein α-synuclein. α-synuclein is considered an intrinsically disordered 14 kDa monomer, and although poorly understood, its transition to higher-order multimeric species may play central roles in healthy neurons and during Parkinson’s disease pathogenesis. In this study, we demonstrate that α-synuclein exists as defined, subcellular-specific species that change characteristics in response to oxidative stress in neuroblastoma cells and in response to Parkinson’s disease pathogenesis in human cerebellum and frontal cortex. We further show that the phosphorylation patterns of different α-synuclein species are subcellular specific and dependent on the oxidative environment. Using high-performance liquid chromatography and mass spectrometry, we identify a Parkinson’s disease enriched, cytosolic ~36-kDa α-synuclein species which can be recapitulated in Parkinson’s disease model neuroblastoma cells. The characterization of subcellular-specific α-synuclein features in neurodegeneration will allow for the identification of neurotoxic α-synuclein species, which represent prime targets to reduce α-synuclein pathogenicity.

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Abbreviations

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

a-syn:

α-synuclein

HPLC:

High-performance liquid chromatography

LDH:

Lactate dehydrogenase

EGFR:

Epidermal growth factor receptor

Tim23:

Translocase of the inner membrane 23

HEK293:

Human embryonic 293 cells

Wt:

Wild type

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Acknowledgements

This research was funded by The Norwegian Research Council, The Western Norway Regional Health Authority, St. John’s University, The Norwegian Centre for Movement Disorders, The Norwegian Parkinson’s Association, and National Institutes of Health Shared Instrumentation Grant S10 RR027990 and P30 NS050276 from NINDS. We thank Dr. Lashuel for providing p-S129 and p-S87 monoclonal antibodies and for purified a-syn. We thank the New York Brain Bank for providing frozen cerebellum from post-mortem PD patients.

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Authors and Affiliations

  1. Department of Biological Sciences, St. John’s University, New York, NY, 11349, USA

    Rashed Abdullah, Ketan S. Patil, Benjamin Rosen, Ramavati Pal, Shubhangi Prabhudesai, Sungsu Lee, Indranil Basak, Peter Yang, Keith Panick & Simon G. Møller

  2. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY, 10016, USA

    Esthelle Hoedt & Thomas A. Neubert

  3. Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, 10016, USA

    Esthelle Hoedt & Thomas A. Neubert

  4. Department of Chemistry, York College of the City University of New York, New York, NY, 11451, USA

    Hsin-Pin Ho & Emmanuel Chang

  5. Center for Mitochondrial Medicine and Neurogenetics, Department of Neurology, Haukeland University Hospital, 5021, Bergen, Norway

    Charalampos Tzoulis

  6. The Norwegian Centre for Movement Disorders, Stavanger University Hospital, 4068, Stavanger, Norway

    Jan Petter Larsen, Guido Alves & Simon G. Møller

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  1. Rashed Abdullah
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Abdullah, R., Patil, K.S., Rosen, B. et al. Subcellular Parkinson’s Disease-Specific Alpha-Synuclein Species Show Altered Behavior in Neurodegeneration. Mol Neurobiol 54, 7639–7655 (2017). https://doi.org/10.1007/s12035-016-0266-8

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