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Molecular Neurobiology

, Volume 54, Issue 10, pp 7639–7655 | Cite as

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

  • Rashed Abdullah
  • Ketan S. Patil
  • Benjamin Rosen
  • Ramavati Pal
  • Shubhangi Prabhudesai
  • Sungsu Lee
  • Indranil Basak
  • Esthelle Hoedt
  • Peter Yang
  • Keith Panick
  • Hsin-Pin Ho
  • Emmanuel Chang
  • Charalampos Tzoulis
  • Jan Petter Larsen
  • Thomas A. Neubert
  • Guido Alves
  • Simon G. MøllerEmail author
Article

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.

Keywords

Alpha-synuclein Multimers Oxidative stress Parkinson’s disease Fractionation 

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

Notes

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.

Supplementary material

12035_2016_266_MOESM1_ESM.tif (1 mb)
Figure S1 (TIFF 1 mb)
12035_2016_266_MOESM2_ESM.docx (62 kb)
Table S1 (DOCX 61 kb)

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Rashed Abdullah
    • 1
  • Ketan S. Patil
    • 1
  • Benjamin Rosen
    • 1
  • Ramavati Pal
    • 1
  • Shubhangi Prabhudesai
    • 1
  • Sungsu Lee
    • 1
  • Indranil Basak
    • 1
  • Esthelle Hoedt
    • 2
    • 3
  • Peter Yang
    • 1
  • Keith Panick
    • 1
  • Hsin-Pin Ho
    • 4
  • Emmanuel Chang
    • 4
  • Charalampos Tzoulis
    • 5
  • Jan Petter Larsen
    • 6
  • Thomas A. Neubert
    • 2
    • 3
  • Guido Alves
    • 6
  • Simon G. Møller
    • 1
    • 6
    Email author
  1. 1.Department of Biological SciencesSt. John’s UniversityNew YorkUSA
  2. 2.Kimmel Center for Biology and Medicine at the Skirball InstituteNew York University School of MedicineNew YorkUSA
  3. 3.Department of Biochemistry and Molecular PharmacologyNew York University School of MedicineNew YorkUSA
  4. 4.Department of ChemistryYork College of the City University of New YorkNew YorkUSA
  5. 5.Center for Mitochondrial Medicine and Neurogenetics, Department of NeurologyHaukeland University HospitalBergenNorway
  6. 6.The Norwegian Centre for Movement DisordersStavanger University HospitalStavangerNorway

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