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Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members (JPH1-JPH4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles and in neurons. Moreover, mutations in the humanJPH2gene are associated with hypertrophic and dilated cardiomyopathies; mutations inJPH3are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereasJPH1acts as a genetic modifier in Charcot-Marie-Tooth 2K peripheral neuropathy.Drosophila melanogasterhas a singlejunctophilin(jp) gene, as is the case in all invertebrates, which might retain equivalent functions of the four homologous JPH genes present in mammalian genomes. Therefore, owing to the lack of putatively redundant genes, ajpDrosophilamodel could provide an excellent platform to model the Junctophilin-related diseases, to discover the ancestral functions of the JPH proteins and to reveal new pathways. By up- and downregulation of Jp in a tissue-specific manner inDrosophila, we show that altering its levels of expression produces a phenotypic spectrum characterized by muscular deficits, dilated cardiomyopathy and neuronal alterations. Importantly, our study has demonstrated that Jp modifies the neuronal degeneration in aDrosophilamodel of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, thisDrosophilamodel has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts.

Original publication




Journal article


Dis Model Mech

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Cardiomyopathy, Drosophila, Huntington's disease, Junctophilin, Notch