Intrastriatal alpha-synuclein fibrils in monkeys: Spreading, imaging and neuropathological changes

Yaping Chu, Scott Muller, Adriana Tavares, Olivier Barret, David Alagille, John Seibyl, Gilles Tamagnan, Ken Marek, Kelvin C. Luk, John Q. Trojanowski, Virginia M.Y. Lee, Jeffrey H. Kordower

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Several studies have demonstrated that intrastriatal injections of fibrillar α-synuclein in rodent brain induced a Parkinson's diseaselike propagation of Lewy body pathology with significant nigrostriatal neurodegeneration. This study evaluated the pathological features when exogenous α-synuclein preformed fibrils were injected into the putamen of non-human primates. Eight cynomolgus monkeys received unilateral intraputamen injections of α-synuclein preformed fibrils and four monkeys received sham surgery. Monkeys were assessed with 123I-PE2I single-photon emission computerized tomography scans targeting the dopamine transprter at baseline, 3, 6, 9, 12, and 15 months. Imaging revealed a robust increase in dopamine transporter binding, an effect confirmed by port-mortem immunohistochemical analyses, suggesting that upregulation of dopamine transporter occurs as part of an early pathological process. Histochemistry and immunohistochemistry revealed that α-synuclein preformed fibrils injections into the putamen induced intraneuronal inclusions positive for phosphorylated α-synuclein in ipsilateral substantia nigra and adjacent to the injection site. α-Synuclein inclusions were thioflavin-S-positive suggesting that the inclusions induced by α-synuclein preformed fibrils exhibited pathological properties similar to amyloid-like Lewy body pathology in Parkinson's disease brains. The α-synuclein preformed fibrils resulted in Lewy pathology in the ipsilateral substantia nigra with significant reduction (-29.30%) of dopaminergic neurons as compared with controls. Nigral neurons with α-synuclein inclusions exhibited a phenotypic downregulation of the dopamine markers tyrosine hydroxylase and Nurr1. Taken together, our findings demonstrate that α-synuclein preformed fibrils induce a synucleinopathy in non-human primates with authentic Lewy pathology and nigrostriatal changes indicative of early Parkinson's disease.

Original languageEnglish (US)
Pages (from-to)3565-3579
Number of pages15
JournalBrain
Volume142
Issue number11
DOIs
StatePublished - Nov 1 2019
Externally publishedYes

Keywords

  • Lewy bodies
  • Neurodegeneration
  • Nigrostriatal system
  • Propagation
  • α-synuclein

ASJC Scopus subject areas

  • Clinical Neurology

Fingerprint

Dive into the research topics of 'Intrastriatal alpha-synuclein fibrils in monkeys: Spreading, imaging and neuropathological changes'. Together they form a unique fingerprint.

Cite this