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BTBD9 and dopaminergic dysfunction in the pathogenesis of restless legs syndrome

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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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Acknowledgements

We would like to thank Dr. Shohei Mitani for the hpo-9(tm3719) strain, Dr. Lin Zhang, Chad C. Cheetham, Sung Min Han, Jack Vibbert, Pauline Cottee, Jessica Winek, and Hieu Hoang for their technical assistance and stimulating discussions. This work was supported by a grant from Restless Legs Syndrome Foundation (2015 RLS Research Grants), and startup funds from the Departments of Neurology at UAB and UF, and the National Institutes of Health [Grants NS54246, NS57098, NS65273, NS72872, NS74423, and NS82244]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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  1. Department of Neurology, Norman Fixel Institute for Neurological Diseases, College of Medicine, University of Florida, PO Box 100236, Gainesville, FL, 32610-0236, USA

    Shangru Lyu, Hong Xing, Mark P. DeAndrade, Fumiaki Yokoi & Yuqing Li

  2. Department of Aging and Geriatric Research, College of Medicine, University of Florida, Gainesville, FL, 32610, USA

    Yi Sheng & Rui Xiao

  3. Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, AL, 35294, USA

    Atbin Doroodchi, Youfeng Yang & Michael A. Miller

  4. Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, NC, 27834, USA

    Tracy L. Johnson & Stefan Clemens

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Lyu, S., Doroodchi, A., Xing, H. et al. BTBD9 and dopaminergic dysfunction in the pathogenesis of restless legs syndrome. Brain Struct Funct 225, 1743–1760 (2020). https://doi.org/10.1007/s00429-020-02090-x

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