A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration

[EN] Charcot-Marie-Tooth disease is a rare peripheral neuropathy for which there is no specific treatment. Some forms of Charcot-Marie-Tooth are due to mutations in the GDAP1 gene. A striking feature of mutations in GDAP1 is that they have a variable clinical manifestation, according to disease onset and progression, histology and mode of inheritance. Studies in cellular and animal models have revealed a role of GDAP1 in mitochondrial morphology and distribution, calcium homeostasis and oxidative stress. To get a better understanding of the disease mechanism we have generated models of over-expression and RNA interference of the Drosophila Gdapl gene. In order to get an overview about the c…

Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot–Marie–Tooth neuropathy

One of the genes involved in Charcot-Marie-Tooth (CMT) disease, an inherited peripheral neuropathy, is GDAP1. In this work, we show that there is a true ortholog of this gene in Drosophila, which we have named Gdap1. By up- and down-regulation of Gdap1 in a tissue-specific manner, we show that altering its levels of expression produces changes in mitochondrial size, morphology and distribution, and neuronal and muscular degeneration. Interestingly, muscular degeneration is tissue-autonomous and not dependent on innervation. Metabolic analyses of our experimental genotypes suggest that alterations in oxidative stress are not a primary cause of the neuromuscular degeneration but a long-term c…

Nuevos modelos y mecanismos moleculares en la enfermedad de Charcot-Marie-Tooth causada por mutaciones en GDAP1

Uno de los genes implicados en la enfermedad de Charcot Marie Tooth, una neuropatia periferica hereditaria, es GDAP1, que codifica para una proteina anclada a la membrana mitocondrial externa. El gen de Drosophila CG4623 es el ortologo de GDAP1 humano, y lo hemos renombrado como Gdap1. La sobreexpresion y silenciamiento de Gdap1, de manera tejido especifica, provoca una degeneracion neuronal y muscular. Ademas, se observan alteraciones en el tamano, morfologia y distribucion mitocondrial. El estudio de diferentes aspectos moleculares indica que los cambios en el estres oxidativo solo ocurren a largo plazo y no son una causa primaria. El estudio metabolomico a traves de la resonancia magneti…

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

[EN] 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 C…

Corrigendum to “A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration” [Biochim. Biophys. Acta 1863 (2017) 801–809]