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

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Harvard

Herborg, F, Jensen, KL, Tolstoy, S, Arends, NV, Posselt, LP, Shekar, A, Aguilar, JI, Lund, VK, Erreger, K, Rickhag, M, Lycas, MD, Lonsdale, MN, Rahbek-Clemmensen, T, Sørensen, AT, Newman, AH, Løkkegaard, A, Kjaerulff, O, Werge, T, Møller, LB, Matthies, HJ, Galli, A, Hjermind, LE & Gether, U 2021, 'Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease', JCI Insight, bind 6, nr. 18, e151496. https://doi.org/10.1172/jci.insight.151496

APA

Herborg, F., Jensen, K. L., Tolstoy, S., Arends, N. V., Posselt, L. P., Shekar, A., Aguilar, J. I., Lund, V. K., Erreger, K., Rickhag, M., Lycas, M. D., Lonsdale, M. N., Rahbek-Clemmensen, T., Sørensen, A. T., Newman, A. H., Løkkegaard, A., Kjaerulff, O., Werge, T., Møller, L. B., ... Gether, U. (2021). Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. JCI Insight, 6(18), [e151496]. https://doi.org/10.1172/jci.insight.151496

CBE

Herborg F, Jensen KL, Tolstoy S, Arends NV, Posselt LP, Shekar A, Aguilar JI, Lund VK, Erreger K, Rickhag M, Lycas MD, Lonsdale MN, Rahbek-Clemmensen T, Sørensen AT, Newman AH, Løkkegaard A, Kjaerulff O, Werge T, Møller LB, Matthies HJ, Galli A, Hjermind LE, Gether U. 2021. Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. JCI Insight. 6(18):Article e151496. https://doi.org/10.1172/jci.insight.151496

MLA

Vancouver

Author

Herborg, Freja ; Jensen, Kathrine L ; Tolstoy, Sasha ; Arends, Natascha V ; Posselt, Leonie P ; Shekar, Aparna ; Aguilar, Jenny I ; Lund, Viktor K ; Erreger, Kevin ; Rickhag, Mattias ; Lycas, Matthew D ; Lonsdale, Markus N ; Rahbek-Clemmensen, Troels ; Sørensen, Andreas T ; Newman, Amy H ; Løkkegaard, Annemette ; Kjaerulff, Ole ; Werge, Thomas ; Møller, Lisbeth B ; Matthies, Heinrich Jg ; Galli, Aurelio ; Hjermind, Lena E ; Gether, Ulrik. / Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. I: JCI Insight. 2021 ; Bind 6, Nr. 18.

Bibtex

@article{e648cce3261c40d4b670c360ad9952fe,
title = "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.",
author = "Freja Herborg and Jensen, {Kathrine L} and Sasha Tolstoy and Arends, {Natascha V} and Posselt, {Leonie P} and Aparna Shekar and Aguilar, {Jenny I} and Lund, {Viktor K} and Kevin Erreger and Mattias Rickhag and Lycas, {Matthew D} and Lonsdale, {Markus N} and Troels Rahbek-Clemmensen and S{\o}rensen, {Andreas T} and Newman, {Amy H} and Annemette L{\o}kkegaard and Ole Kjaerulff and Thomas Werge and M{\o}ller, {Lisbeth B} and Matthies, {Heinrich Jg} and Aurelio Galli and Hjermind, {Lena E} and Ulrik Gether",
year = "2021",
month = sep,
day = "22",
doi = "10.1172/jci.insight.151496",
language = "English",
volume = "6",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",
number = "18",

}

RIS

TY - JOUR

T1 - Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease

AU - Herborg, Freja

AU - Jensen, Kathrine L

AU - Tolstoy, Sasha

AU - Arends, Natascha V

AU - Posselt, Leonie P

AU - Shekar, Aparna

AU - Aguilar, Jenny I

AU - Lund, Viktor K

AU - Erreger, Kevin

AU - Rickhag, Mattias

AU - Lycas, Matthew D

AU - Lonsdale, Markus N

AU - Rahbek-Clemmensen, Troels

AU - Sørensen, Andreas T

AU - Newman, Amy H

AU - Løkkegaard, Annemette

AU - Kjaerulff, Ole

AU - Werge, Thomas

AU - Møller, Lisbeth B

AU - Matthies, Heinrich Jg

AU - Galli, Aurelio

AU - Hjermind, Lena E

AU - Gether, Ulrik

PY - 2021/9/22

Y1 - 2021/9/22

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85116159480&partnerID=8YFLogxK

U2 - 10.1172/jci.insight.151496

DO - 10.1172/jci.insight.151496

M3 - Journal article

C2 - 34375312

VL - 6

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 18

M1 - e151496

ER -

ID: 67621523