Functional and neuropathological changes induced by injection of distinct alpha-synuclein strains: A pilot study in non-human primates

https://doi.org/10.1016/j.nbd.2023.106086Get rights and content
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Highlights

  • α-synuclein strain structure dictates pathologic propagation patterns in NHPs.

  • Distinct α-synuclein strains induce different metabolic changes in vivo in NHPs.

  • α-Synuclein intra-striatal injection induces dopaminergic changes in NHP brain.

Abstract

The role of alpha-synuclein in Parkinson's disease has been heavily investigated since its discovery as a component of Lewy bodies. Recent rodent data demonstrate that alpha-synuclein strain structure is critical for differential propagation and toxicity.

Based on these findings, we have compared, for the first time, in this pilot study, the capacity of two alpha-synuclein strains and patient-derived Lewy body extracts to model synucleinopathies after intra-putaminal injection in the non-human primate brain. Functional alterations triggered by these injections were evaluated in vivo using glucose positron emission tomography imaging. Post-mortem immunohistochemical and biochemical analyses were used to detect neuropathological alterations in the dopaminergic system and alpha-synuclein pathology propagation.

In vivo results revealed a decrease in glucose metabolism more pronounced in alpha-synuclein strain-injected animals. Histology showed a decreased number of dopaminergic tyrosine hydroxylase-positive cells in the substantia nigra to different extents according to the inoculum used. Biochemistry revealed that alpha-synuclein-induced aggregation, phosphorylation, and propagation in different brain regions are strain-specific.

Our findings show that distinct alpha-synuclein strains can induce specific patterns of synucleinopathy in the non-human primate, changes in the nigrostriatal pathway, and functional alterations that resemble early-stage Parkinson's disease.

Keywords

Non-human primates
Alpha-synuclein strains
Lewy bodies
Nigrostriatal alterations
Alpha-synuclein propagation

Abbreviations

[18F]-FDG
[18F]-fluoro-deoxy-glucose
α-syn
Alpha-synuclein
FIB
Fibrils
GP
Globus Pallidus
LB
Lewy Bodies
moPI
Months Post-injection
MSA
Multiple System Atrophy
NHP
Non-human Primate
PD
Parkinson's Disease
PMCA
Misfolding Cyclic Amplification
RIB
Ribbons
ROI
Region of Interest
SNpc
Substantia Nigra Pars Compacta
TH
Tyrosine Hydroxylase

Data availability

The data supporting this study's findings are available from the corresponding author upon request.

Cited by (0)

1

Second and third authors contributed equally to this work

2

Last two authors contributed equally to this work