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Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.

ABSTRACT: Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular dopamine levels, but the genetic and mechanistic link between DAT function and dopamine-related pathologies is not clear. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here, we use clinical information, neuroimaging, and large-scale exome-sequencing data to uncover the occurrence and phenotypic spectrum of a DAT coding variant, DAT-K619N, which localizes to the critical C-terminal PSD-95/Discs-large/ZO-1 homology-binding motif of human DAT (hDAT). We identified the rare but recurrent hDAT-K619N variant in exome-sequenced samples of patients with neuropsychiatric diseases and a patient with early-onset neurodegenerative parkinsonism and comorbid neuropsychiatric disease. In cell cultures, hDAT-K619N displayed reduced uptake capacity, decreased surface expression, and accelerated turnover. Unilateral expression in mouse nigrostriatal neurons revealed differential effects of hDAT-K619N and hDAT-WT on dopamine-directed behaviors, and hDAT-K619N expression in Drosophila led to impairments in dopamine transmission with accompanying hyperlocomotion and age-dependent disturbances of the negative geotactic response. Moreover, cellular studies and viral expression of hDAT-K619N in mice demonstrated a dominant-negative effect of the hDAT-K619N mutant. Summarized, our results suggest that hDAT-K619N can effectuate dopamine dysfunction of pathological relevance in a dominant-negative manner.

SUBMITTER: Herborg F

PROVIDER: S-EPMC8492322 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.

Herborg Freja F Jensen Kathrine L KL Tolstoy Sasha S Arends Natascha V NV Posselt Leonie P LP Shekar Aparna A Aguilar Jenny I JI Lund Viktor K VK Erreger Kevin K Rickhag Mattias M Lycas Matthew D MD Lonsdale Markus N MN Rahbek-Clemmensen Troels T Sørensen Andreas T AT Newman Amy H AH Løkkegaard Annemette A Kjærulff Ole O Werge Thomas T Møller Lisbeth B LB Møller Lisbeth B LB Matthies Heinrich Jg HJ Galli Aurelio A Hjermind Lena E LE Gether Ulrik U

JCI insight 20210922 18

Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular dopamine levels, but the genetic and mechanistic link between DAT function and dopamine-related pathologies is not clear. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here, we use clinical information, neuroimaging, and large-scale exome-sequencing data to uncover the occurrence and phen ...[more]

PMID: 34375312

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Project description:PurposeThis work attempts to decode the discriminative information in dopamine transporter (DAT) imaging using deep learning for the differential diagnosis of parkinsonism.MethodsThis study involved 1017 subjects who underwent DAT PET imaging ([11C]CFT) including 43 healthy subjects and 974 parkinsonian patients with idiopathic Parkinson's disease (IPD), multiple system atrophy (MSA) or progressive supranuclear palsy (PSP). We developed a 3D deep convolutional neural network to learn distinguishable DAT features for the differential diagnosis of parkinsonism. A full-gradient saliency map approach was employed to investigate the functional basis related to the decision mechanism of the network. Furthermore, deep-learning-guided radiomics features and quantitative analysis were compared with their conventional counterparts to further interpret the performance of deep learning.ResultsThe proposed network achieved area under the curve of 0.953 (sensitivity 87.7%, specificity 93.2%), 0.948 (sensitivity 93.7%, specificity 97.5%), and 0.900 (sensitivity 81.5%, specificity 93.7%) in the cross-validation, together with sensitivity of 90.7%, 84.1%, 78.6% and specificity of 88.4%, 97.5% 93.3% in the blind test for the differential diagnosis of IPD, MSA and PSP, respectively. The saliency map demonstrated the most contributed areas determining the diagnosis located at parkinsonism-related regions, e.g., putamen, caudate and midbrain. The deep-learning-guided binding ratios showed significant differences among IPD, MSA and PSP groups (P < 0.001), while the conventional putamen and caudate binding ratios had no significant difference between IPD and MSA (P = 0.24 and P = 0.30). Furthermore, compared to conventional radiomics features, there existed average above 78.1% more deep-learning-guided radiomics features that had significant differences among IPD, MSA and PSP.ConclusionThis study suggested the developed deep neural network can decode in-depth information from DAT and showed potential to assist the differential diagnosis of parkinsonism. The functional regions supporting the diagnosis decision were generally consistent with known parkinsonian pathology but provided more specific guidance for feature selection and quantitative analysis.

Dataset Information

Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.

Publications

Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease.

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