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

Abstract

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 JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in Charcot–Marie–Tooth 2K peripheral neuropathy. Drosophila melanogaster has a single junctophilin (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, a jp Drosophila 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 Drosophila, 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 Drosophila model of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, this Drosophila model has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts.

Molecular characterization of western corn rootworm pyrethroid resistance

“…Junctophilin, overexpressed in the field‐derived pyrethroid‐resistant WCR population, is a protein commonly found in human neurons, where it is involved in coupling membrane neurotransmitter receptors and intracellular channels 88 . A study showed that a junctophilin gene from Drosophila melanogaster Meigen is functionally equivalent to mammalian homologues and that flies with altered junctophilin expression also have marked neuronal alterations 89 . The predicted E3 ubiquitin‐protein ligase and neprilysin, overexpressed in the laboratory‐selected pyrethroid‐resistant WCR populations, also play a role in the nervous system of insects.…”

Characterization of pyrethroid resistance in the western corn rootwormDiabrotica virgifera virgiferaLeConte

“…Junctophilin, overexpressed in the field-derived pyrethroid-resistant WCR population, is a protein commonly found in human excitable cells such as neurons where it is involved in coupling membrane neurotransmitter receptors and intracellular channels (Landstrom et al 2014). A study showed that a junctophilin gene from fruit fly Drosophila melanogaster Meigen is functionally equivalent to mammal homologues and that flies with altered junctophilin expression also have marked neuronal alterations (Calpena et al 2018). The predicted E3 ubiquitin-protein ligase and neprilysin, overexpressed in the lab-selected pyrethroidresistant WCR populations, also play a role in the nervous system of insects.…”

Post-Developmental Roles of Notch Signaling in the Nervous System

“…HD is caused by poly-glutamine (polyQ) expansions in the Huntingtin ( HTT ) gene. Using a fly model of HD in which mutant Huntingtin protein was overexpressed in the eye causing an age-dependent rough eye phenotype, Calpena et al found that knock-down of junctophilin ( jp ) enhances this phenotype while overexpression of jp suppresses this defect [ 217 ]. In the same paper, the authors noted that ubiquitous knock-down of jp causes bristle and wing vein phenotypes that are reminiscent of Notch LOF defects, and further showed that jp genetically interacts with Delta mutants.…”