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

Brain. 2019 Nov 1;142(11):3565-3579. doi: 10.1093/brain/awz296.

Abstract

Several studies have demonstrated that intrastriatal injections of fibrillar α-synuclein in rodent brain induced a Parkinson's disease-like 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.

Keywords: Lewy bodies; neurodegeneration; nigrostriatal system; propagation; α-synuclein.

MeSH terms

  • Animals
  • Cell Count
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Dopaminergic Neurons / pathology
  • Immunohistochemistry
  • Lewy Bodies / pathology
  • Macaca fascicularis
  • Microinjections
  • Neostriatum / diagnostic imaging
  • Neostriatum / metabolism*
  • Neostriatum / pathology*
  • Nuclear Receptor Subfamily 4, Group A, Member 2 / metabolism
  • Putamen
  • Substantia Nigra / metabolism
  • Substantia Nigra / pathology
  • Synucleinopathies / diagnostic imaging
  • Synucleinopathies / metabolism*
  • Synucleinopathies / pathology*
  • Tomography, Emission-Computed, Single-Photon
  • Tyrosine 3-Monooxygenase / metabolism
  • alpha-Synuclein / administration & dosage
  • alpha-Synuclein / metabolism*

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Nuclear Receptor Subfamily 4, Group A, Member 2
  • alpha-Synuclein
  • Tyrosine 3-Monooxygenase