AUTHOR=Morley Victoria , Dolt Karamjit Singh , Alcaide-Corral Carlos J. , Walton Tashfeen , Lucatelli Christophe , Mashimo Tomoji , Tavares Adriana A. S. , Kunath Tilo 

TITLE=In vivo18F-DOPA PET imaging identifies a dopaminergic deficit in a rat model with a G51D α-synuclein mutation

JOURNAL=Frontiers in Neuroscience

VOLUME=17

YEAR=2023

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1095761

DOI=10.3389/fnins.2023.1095761

ISSN=1662-453X

ABSTRACT=<p>Parkinson’s disease (PD) is a neurodegenerative condition with several major hallmarks, including loss of <italic>substantia nigra</italic> neurons, reduction in striatal dopaminergic function, and formation of α-synuclein-rich Lewy bodies. Mutations in <italic>SNCA</italic>, encoding for α-synuclein, are a known cause of familial PD, and the G51D mutation causes a particularly aggressive form of the condition. CRISPR/Cas9 technology was used to introduce the G51D mutation into the endogenous rat <italic>SNCA</italic> gene. <italic>SNCA</italic><sup>G51D/+</sup> and <italic>SNCA</italic><sup>G51D/G51D</sup> rats were born in Mendelian ratios and did not exhibit any severe behavourial defects. <italic>L</italic>-3,4-dihydroxy-6-<sup>18</sup>F-fluorophenylalanine (<sup>18</sup>F-DOPA) positron emission tomography (PET) imaging was used to investigate this novel rat model. Wild-type (WT), <italic>SNCA</italic><sup>G51D/+</sup> and <italic>SNCA</italic><sup>G51D/G51D</sup> rats were characterized over the course of ageing (5, 11, and 16 months old) using <sup>18</sup>F-DOPA PET imaging and kinetic modelling. We measured the influx rate constant (<italic>K<sub>i</sub></italic>) and effective distribution volume ratio (<italic>EDVR</italic>) of <sup>18</sup>F-DOPA in the striatum relative to the cerebellum in WT, <italic>SNCA</italic><sup>G51D/+</sup> and <italic>SNCA</italic><sup>G51D/G51D</sup> rats. A significant reduction in <italic>EDVR</italic> was observed in <italic>SNCA</italic><sup>G51D/G51D</sup> rats at 16 months of age indicative of increased dopamine turnover. Furthermore, we observed a significant asymmetry in <italic>EDVR</italic> between the left and right striatum in aged <italic>SNCA</italic><sup>G51D/G51D</sup> rats. The increased and asymmetric dopamine turnover observed in the striatum of aged <italic>SNCA</italic><sup>G51D/G51D</sup> rats reflects one aspect of prodromal PD, and suggests the presence of compensatory mechanisms. <italic>SNCA</italic><sup>G51D</sup> rats represent a novel genetic model of PD, and kinetic modelling of <sup>18</sup>F-DOPA PET data has identified a highly relevant early disease phenotype.</p>