BTBD9 and dopaminergic dysfunction in the pathogenesis of restless legs syndrome

AbstractRestless 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 inBTBD9 to a higher risk of RLS. Knockout ofBTBD9 homolog in mice (Btbd9) and fly results in RLS-like phenotypes. A dysfunctional dopaminergic system is associated with RLS. However, the function ofBTBD9 in the dopaminergic system and RLS is not clear. Here, we made use of the simpleCaenorhabditis elegans nervous system. Loss ofhpo-9, the worm homolog ofBTBD9, resulted in hyperactive egg-laying behavior. Analysis of genetic interactions betweenhpo-9 and genes for dopamine receptors (dop-1, dop-3) indicated thathpo-9 anddop-1 worked similarly. Reporter assays ofdop-1 anddop-3 revealed thathpo-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 theBtbd9 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 theBtbd9 knockout mice. Finally, we generated and characterized the  dopamine neuron-specificBtbd9 knockout mice and detected an  active-phase sleepiness, suggesting that dopamine neuron-specific loss ofBtbd9 is sufficient to disturb the...
Source: Anatomy and Embryology - Category: Anatomy Source Type: research