Details

Autor(en) / Beteiligte

• 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
• Kjærulff, Ole
• Werge, Thomas
• Møller, Lisbeth B
• Matthies, Heinrich Jg
• Galli, Aurelio
• Hjermind, Lena E
• Gether, Ulrik

Titel

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

Ist Teil von

• JCI insight, 2021-09, Vol.6 (18)

Ort / Verlag

United States: American Society for Clinical Investigation

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Electronic Journals Library

Beschreibungen/Notizen

• 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.