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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. / Herborg, Freja; Jensen, Kathrine L.; Tolstoy, Sasha; Arends, Natascha; Posselt, Leonie P.; Shekar, Aparna; Aguilar, Jenny; Lund, Viktor K.; Erreger, Kevin; Rickhag, Mattias; Lycas, Matthew D.; Lonsdale, Markus N.; Rahbek-Clemmensen, Troels; Sorensen, Andreas T.; Newman, Amy H.; Lokkegaard, Annemette; Kjaerulff, Ole; Werge, Thomas; Moller, Lisbeth B.; Matthies, Heinrich J. G.; Galli, Aurelio; Hjermind, Lena E.; Gether, Ulrik; IPSYCH Researchers.

In: JCI insight, Vol. 6, No. 18, 151496, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Herborg, F, Jensen, KL, Tolstoy, S, Arends, N, Posselt, LP, Shekar, A, Aguilar, J, Lund, VK, Erreger, K, Rickhag, M, Lycas, MD, Lonsdale, MN, Rahbek-Clemmensen, T, Sorensen, AT, Newman, AH, Lokkegaard, A, Kjaerulff, O, Werge, T, Moller, LB, Matthies, HJG, Galli, A, Hjermind, LE, Gether, U & IPSYCH Researchers 2021, 'Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease', JCI insight, vol. 6, no. 18, 151496. https://doi.org/10.1172/jci.insight.151496

APA

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

Vancouver

Herborg F, Jensen KL, Tolstoy S, Arends N, Posselt LP, Shekar A et al. Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. JCI insight. 2021;6(18). 151496. https://doi.org/10.1172/jci.insight.151496

Author

Herborg, Freja ; Jensen, Kathrine L. ; Tolstoy, Sasha ; Arends, Natascha ; Posselt, Leonie P. ; Shekar, Aparna ; Aguilar, Jenny ; Lund, Viktor K. ; Erreger, Kevin ; Rickhag, Mattias ; Lycas, Matthew D. ; Lonsdale, Markus N. ; Rahbek-Clemmensen, Troels ; Sorensen, Andreas T. ; Newman, Amy H. ; Lokkegaard, Annemette ; Kjaerulff, Ole ; Werge, Thomas ; Moller, Lisbeth B. ; Matthies, Heinrich J. G. ; Galli, Aurelio ; Hjermind, Lena E. ; Gether, Ulrik ; IPSYCH Researchers. / Identifying dominant-negative actions of a dopamine transporter variant in patients with parkinsonism and neuropsychiatric disease. In: JCI insight. 2021 ; Vol. 6, No. 18.

Bibtex

@article{d13ac0118cf0479d8f70740a36be84e8,
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 hDATWT 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.",
keywords = "SEQUENCE VARIATION, GENE, AMPHETAMINE, TRAFFICKING, MICE, NEUROTRANSMISSION, OLIGOMERIZATION, ARCHITECTURES, HYPERACTIVITY, MUTATIONS",
author = "Freja Herborg and Jensen, {Kathrine L.} and Sasha Tolstoy and Natascha Arends and Posselt, {Leonie P.} and Aparna Shekar and Jenny Aguilar and Lund, {Viktor K.} and Kevin Erreger and Mattias Rickhag and Lycas, {Matthew D.} and Lonsdale, {Markus N.} and Troels Rahbek-Clemmensen and Sorensen, {Andreas T.} and Newman, {Amy H.} and Annemette Lokkegaard and Ole Kjaerulff and Thomas Werge and Moller, {Lisbeth B.} and Matthies, {Heinrich J. G.} and Aurelio Galli and Hjermind, {Lena E.} and Ulrik Gether and {IPSYCH Researchers}",
year = "2021",
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

AU - Posselt, Leonie P.

AU - Shekar, Aparna

AU - Aguilar, Jenny

AU - Lund, Viktor K.

AU - Erreger, Kevin

AU - Rickhag, Mattias

AU - Lycas, Matthew D.

AU - Lonsdale, Markus N.

AU - Rahbek-Clemmensen, Troels

AU - Sorensen, Andreas T.

AU - Newman, Amy H.

AU - Lokkegaard, Annemette

AU - Kjaerulff, Ole

AU - Werge, Thomas

AU - Moller, Lisbeth B.

AU - Matthies, Heinrich J. G.

AU - Galli, Aurelio

AU - Hjermind, Lena E.

AU - Gether, Ulrik

AU - IPSYCH Researchers

PY - 2021

Y1 - 2021

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 hDATWT 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 hDATWT 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.

KW - SEQUENCE VARIATION

KW - GENE

KW - AMPHETAMINE

KW - TRAFFICKING

KW - MICE

KW - NEUROTRANSMISSION

KW - OLIGOMERIZATION

KW - ARCHITECTURES

KW - HYPERACTIVITY

KW - MUTATIONS

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 - 151496

ER -

ID: 281594862