PROJECT: JTC2015: SMART

The aim of this proposal is to gain a better understanding of neurodevelopmental abnormalities in Restless Legs Syndrome (RLS). Despite its high prevalence and significant morbidity, awareness is still low and the disease remains underdiagnosed. Limited long-term efficacy of existing drugs creates an urgent need to enhance understanding of disease mechanisms and develop better treatments. We will investigate the RLS-associated homeobox gene MEIS1 in the development and function of striatal sensorimotor neurocircuitry and delineate the consequences of MEIS1 loss of function. To identify key neuronal cells/pathways and drug targets, and personalized treatments, we will use transgenic mouse models, investigating developmental cell specification and lineage tracing, neuroanatomy, transcriptomics, proteomics, transcription factor binding and behavior. We will integrate analyses of patient genotypes and phenotypes. Our approach is only possible through the closely integrated research plan of three groups highly specialized in the complementary areas: i) phenotype and human genetics of RLS, ii) developmental function of the key RLS-associated gene MEIS1 and iii) developmental biology of the striatum, an RLS-related brain area. Knowledge gained from these studies will provide mechanistic insight into the pathogenesis of RLS and pave the way for improved therapeutic approaches for this debilitating disease. Moreover, it might have implications for other dopaminergic disorders.