title: Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia.
abstract: Mutations in genes essential for protein homeostasis have been identified in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Why mature neurons should be particularly sensitive to such perturbations is unclear. We identified mutations in Rab8 in a genetic screen for enhancement of an FTD phenotype associated with ESCRT-III dysfunction. Examination of Rab8 mutants or motor neurons expressing a mutant ESCRT-III subunit, CHMP2B(Intron5), at the Drosophila melanogaster neuromuscular junction synapse revealed synaptic overgrowth and endosomal dysfunction. Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2B(Intron5). In Rab8 mutant synapses, c-Jun N-terminal kinase (JNK)/activator protein-1 and TGF-β signaling were overactivated and acted synergistically to potentiate synaptic growth. We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants. Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes.
authors: Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK.
authors: Ryan J H
authors: RJ
authors: West
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605.
authors: Yubing
authors: Y
authors: Lu
authors: Institute of Neurobiology, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico 00901.
authors: Bruno
authors: B
authors: Marie
authors: Department of Neurology, University of Massachusetts Medical School, Worcester, MA 01605.
authors: Fen-Biao
authors: FB
authors: Gao
authors: Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK sean.sweeney@york.ac.uk.
authors: Sean T
authors: ST
authors: Sweeney
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics; D011992:Endosomes / Q000378:metabolism; D057180:Frontotemporal Dementia / Q000235:genetics*; D020558:GTP Phosphohydrolases / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009469:Neuromuscular Junction / Q000235:genetics / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: C543046:CHMP2B protein, Drosophila; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; D056827:Endosomal Sorting Complexes Required for Transport; D009419:Nerve Tissue Proteins; C453299:POSH protein, Drosophila; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D033921:Vesicular Transport Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C000593602:TAK1 protein, Drosophila; D020558:GTP Phosphohydrolases; C000596969:Rab8 protein, Drosophila