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

Autor: Herborg F; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Jensen KL; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Tolstoy S; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Arends NV; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Posselt LP; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Shekar A; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Aguilar JI; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Lund VK; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Erreger K; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA., Rickhag M; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Lycas MD; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Lonsdale MN; Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, Copenhagen, Denmark., Rahbek-Clemmensen T; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Sørensen AT; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Newman AH; National Institute on Drug Abuse Intramural Research Program, NIH, Baltimore, Maryland, USA., Løkkegaard A; Department of Neurology, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark., Kjærulff O; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Werge T; Institute of Biological Psychiatry, Mental Health Services Copenhagen, Copenhagen, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.; Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen, Denmark., Møller LB; Center for Applied Human Genetics, Kennedy Center, Copenhagen University Hospital, Glostrup, Denmark., Matthies HJ; Department of Surgery, University of Alabama, Birmingham, Alabama, USA., Galli A; Department of Surgery, University of Alabama, Birmingham, Alabama, USA., Hjermind LE; Danish Dementia Research Centre, Clinic of Neurogenetics, Department of Neurology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.; Department of Cellular and Molecular Medicine, Section of Neurogenetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Gether U; Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: JCI insight [JCI Insight] 2021 Sep 22; Vol. 6 (18). Date of Electronic Publication: 2021 Sep 22.
DOI: 10.1172/jci.insight.151496
Abstrakt: 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.
Databáze: MEDLINE