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  • Thakur, PoonamLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups (author)

Modeling Parkinson’s disease pathology by combination of fibril seeds and α-synuclein overexpression in the rat brain

  • Article/chapterEnglish2017

Publisher, publication year, extent ...

  • 2017-09-12
  • Proceedings of the National Academy of Sciences,2017

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:643f63a4-b390-42ac-b294-1c3ebe2391fa
  • https://lup.lub.lu.se/record/643f63a4-b390-42ac-b294-1c3ebe2391faURI
  • https://doi.org/10.1073/pnas.1710442114DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • Although a causative role of α-synuclein (α-syn) is well established in Parkinson’s disease pathogenesis, available animal models of synucleinopathy do not replicate the full range of cellular and behavioral changes characteristic of the human disease. This study was designed to generate a more faithful model of Parkinson’s disease by injecting human α-syn fibril seeds into the rat substantia nigra (SN), in combination with adenoassociated virus (AAV)-mediated overexpression of human α-syn, at levels that, by themselves, are unable to induce acute dopamine (DA) neurodegeneration. We show that the ability of human α-syn fibrils to trigger Lewy-like α-synuclein pathology in the affected DA neurons is dramatically enhanced in the presence of elevated levels of human α-syn. This synucleinopathy was fully developed already 10 days after fibril injection, accompanied by progressive degeneration of dopaminergic neurons in SN, neuritic swelling, reduced striatal DA release, and impaired motor behavior. Moreover, a prominent inflammatory response involving both activation of resident microglia and infiltration of CD4+ and CD8+ T lymphocytes was observed. Hypertrophic microglia were found to enclose or engulf cells and processes containing Lewy-like α-syn aggregates. α-Syn aggregates were also observed inside these cells, suggesting transfer of phosphorylated α-syn from the affected nigral neurons. The nigral pathology triggered by fibrils in combination with AAV-mediated overexpression of α-syn reproduced many of the cardinal features of the human disease. The short time span and the distinct sequence of pathological and degenerative changes make this combined approach attractive as an experimental model for the assessment of neuroprotective and disease-modifying strategies.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Breger, Ludivine S.Lund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups(Swepub:lu)med-lib (author)
  • Lundblad, MartinLund University,Lunds universitet,Utvecklings- och regenerativ neurobiologi,Forskargrupper vid Lunds universitet,Developmental and Regenerative Neurobiology,Lund University Research Groups(Swepub:lu)mphy-mlu (author)
  • Wan, Oi WanLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups(Swepub:lu)med-oiw (author)
  • Mattsson, BengtLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups(Swepub:lu)neur-bma (author)
  • Luk, Kelvin C.University of Pennsylvania (author)
  • Lee, Virginia Man YeeUniversity of Pennsylvania (author)
  • Trojanowski, John QUniversity of Pennsylvania (author)
  • Björklund, AndersLund University,Lunds universitet,Neurobiologi,Forskargrupper vid Lunds universitet,Neurobiology,Lund University Research Groups(Swepub:lu)mphy-abj (author)
  • NeurobiologiForskargrupper vid Lunds universitet (creator_code:org_t)

Related titles

  • In:Proceedings of the National Academy of Sciences of the United States of America: Proceedings of the National Academy of Sciences114:39, s. 8284-82930027-8424
  • In:Proceedings of the National Academy of Sciences: Proceedings of the National Academy of Sciences114:39, s. 8284-82931091-6490

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