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Brain. 2019 Oct 3. pii: awz296. doi: 10.1093/brain/awz296. [Epub ahead of print]

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

Author information

1
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
2
Molecular NeuroImaging, LLC New Haven, CT, USA.
3
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
4
Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.

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

PMID:
31580415
DOI:
10.1093/brain/awz296

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