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Victoria Morley1, Karamjit Singh Dolt1, Carlos J Alcaide-Corral2

  • 1Centre for Regenerative Medicine, Institute for Regeneration and Repair, School of Biological Sciences, The University of Edinburgh, Edinburgh, United Kingdom.

Frontiers in Neuroscience
|June 9, 2023
PubMed
Summary
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Newly developed G51D rats carrying the SNCA G51D mutation offer a novel Parkinson's disease (PD) model. Positron emission tomography (PET) imaging revealed early signs of increased dopamine turnover in these rats, suggesting prodromal PD.

Area of Science:

  • Neuroscience
  • Genetics
  • Medical Imaging

Background:

  • Parkinson's disease (PD) is characterized by neuronal loss, reduced dopaminergic function, and Lewy bodies.
  • Mutations in the SNCA gene, particularly G51D, are linked to familial and aggressive forms of PD.
  • Developing accurate animal models is crucial for understanding PD pathogenesis and testing therapies.

Purpose of the Study:

  • To create and characterize a novel rat model of Parkinson's disease using CRISPR/Cas9 technology.
  • To investigate early dopaminergic dysfunction in this model using 18F-DOPA PET imaging and kinetic modeling.
  • To identify prodromal PD phenotypes in the novel SNCAG51D rat model.

Main Methods:

  • CRISPR/Cas9 was used to introduce the G51D mutation into the endogenous rat SNCA gene.
Keywords:
G51D α-synuclein mutationPET imagingParkinson’skinetic modelingrat model

Related Experiment Videos

  • 18F-DOPA positron emission tomography (PET) imaging and kinetic modeling were employed to assess striatal dopaminergic function.
  • Measurements included the influx rate constant (Ki) and effective distribution volume ratio (EDVR) in rats aged 5, 11, and 16 months.

    • Main Results:

    • SNCAG51D/+ and SNCAG51D/G51D rats showed no severe behavioral defects but exhibited altered dopaminergic function with age.
    • A significant reduction in EDVR was observed in SNCAG51D/G51D rats at 16 months, indicating increased dopamine turnover.
    • Asymmetric EDVR between left and right striata was noted in aged SNCAG51D/G51D rats, reflecting prodromal PD aspects.

    Conclusions:

    • SNCAG51D rats represent a valuable new genetic model for Parkinson's disease research.
    • Kinetic modeling of 18F-DOPA PET data successfully identified an early disease phenotype in this model.
    • The observed dopamine turnover changes suggest compensatory mechanisms in the early stages of PD.