The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

• Published in: Disease models & mechanisms Vol. 11; no. 1
• Main Authors: Calpena, Eduardo, López Del Amo, Víctor, Chakraborty, Mouli, Llamusí, Beatriz, Artero, Rubén, Espinós, Carmen, Galindo, Máximo I
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.01.2018; The Company of Biologists
• Subjects: Alleles; Animals; Animals, Genetically Modified; Cardiomyopathy; Disease Models, Animal; Dros; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila melanogaster - ultrastructure; Drosophila Proteins - metabolism; Gene Knockdown Techniques; Genes; Genes, Insect; Genotype; Heart; Huntingtin Protein - metabolism; Huntington's disease; Huntingtons disease; Insects; Junctophilin; Mammals; Mammals - metabolism; Membrane Proteins - metabolism; Muscles - metabolism; Muscles - pathology; Muscles - ultrastructure; Musculoskeletal system; Mutation; Mutation - genetics; Myocardium - metabolism; Myocardium - pathology; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Neurons - metabolism; Notch; Phenotype; Photoreceptor Cells, Invertebrate - metabolism; Proteins; Receptors, Notch - metabolism; Reproducibility of Results; RNA Interference; Signal Transduction; Trinucleotide Repeat Expansion - genetics; Oregon; United States > US; Junctophilin; Huntington's disease; Cardiomyopathy; Drosophila; Notch
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.029082

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 human gene are associated with hypertrophic and dilated cardiomyopathies; mutations in are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas acts as a genetic modifier in Charcot-Marie-Tooth 2K peripheral neuropathy. has a single ( ) 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, a model 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 in , 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 a model of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, this model has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts.