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Brain Structure and Function
Erschienen in: Brain Structure and Function 6/2020

28.05.2020 | Original Article

BTBD9 and dopaminergic dysfunction in the pathogenesis of restless legs syndrome

verfasst von: Shangru Lyu, Atbin Doroodchi, Hong Xing, Yi Sheng, Mark P. DeAndrade, Youfeng Yang, Tracy L. Johnson, Stefan Clemens, Fumiaki Yokoi, Michael A. Miller, Rui Xiao, Yuqing Li

Erschienen in: Brain Structure and Function | Ausgabe 6/2020

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Abstract

Restless legs syndrome (RLS) is characterized by an urge to move legs, usually accompanied by uncomfortable sensations. RLS symptoms generally happen at night and can be relieved by movements. Genetic studies have linked polymorphisms in BTBD9 to a higher risk of RLS. Knockout of BTBD9 homolog in mice (Btbd9) and fly results in RLS-like phenotypes. A dysfunctional dopaminergic system is associated with RLS. However, the function of BTBD9 in the dopaminergic system and RLS is not clear. Here, we made use of the simple Caenorhabditis elegans nervous system. Loss of hpo-9, the worm homolog of BTBD9, resulted in hyperactive egg-laying behavior. Analysis of genetic interactions between hpo-9 and genes for dopamine receptors (dop-1, dop-3) indicated that hpo-9 and dop-1 worked similarly. Reporter assays of dop-1 and dop-3 revealed that hpo-9 knockout led to a significant increase of DOP-3 expression. This appears to be evolutionarily conserved in mice with an increased D2 receptor (D2R) mRNA in the striatum of the Btbd9 knockout mice. Furthermore, the striatal D2R protein was significantly decreased and Dynamin I was increased. Overall, activities of DA neurons in the substantia nigra were not altered, but the peripheral D1R pathway was potentiated in the Btbd9 knockout mice. Finally, we generated and characterized the dopamine neuron-specific Btbd9 knockout mice and detected an active-phase sleepiness, suggesting that dopamine neuron-specific loss of Btbd9 is sufficient to disturb the sleep. Our results suggest that increased activities in the D1R pathway, decreased activities in the D2R pathway, or both may contribute to RLS.
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Metadaten
Titel
BTBD9 and dopaminergic dysfunction in the pathogenesis of restless legs syndrome
verfasst von
Shangru Lyu
Atbin Doroodchi
Hong Xing
Yi Sheng
Mark P. DeAndrade
Youfeng Yang
Tracy L. Johnson
Stefan Clemens
Fumiaki Yokoi
Michael A. Miller
Rui Xiao
Yuqing Li
Publikationsdatum
28.05.2020
Verlag
Springer Berlin Heidelberg
Erschienen in
Brain Structure and Function / Ausgabe 6/2020
Print ISSN: 1863-2653
Elektronische ISSN: 1863-2661
DOI
https://doi.org/10.1007/s00429-020-02090-x

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