title: Disruption of axonal transport perturbs bone morphogenetic protein (BMP)--signaling and contributes to synaptic abnormalities in two neurodegenerative diseases.
abstract: Formation of new synapses or maintenance of existing synapses requires the delivery of synaptic components from the soma to the nerve termini via axonal transport. One pathway that is important in synapse formation, maintenance and function of the Drosophila neuromuscular junction (NMJ) is the bone morphogenetic protein (BMP)-signaling pathway. Here we show that perturbations in axonal transport directly disrupt BMP signaling, as measured by its downstream signal, phospho Mad (p-Mad). We found that components of the BMP pathway genetically interact with both kinesin-1 and dynein motor proteins. Thick vein (TKV) vesicle motility was also perturbed by reductions in kinesin-1 or dynein motors. Interestingly, dynein mutations severely disrupted p-Mad signaling while kinesin-1 mutants showed a mild reduction in p-Mad signal intensity. Similar to mutants in components of the BMP pathway, both kinesin-1 and dynein motor protein mutants also showed synaptic morphological defects. Strikingly TKV motility and p-Mad signaling were disrupted in larvae expressing two human disease proteins; expansions of glutamine repeats (polyQ77) and human amyloid precursor protein (APP) with a familial Alzheimer's disease (AD) mutation (APPswe). Consistent with axonal transport defects, larvae expressing these disease proteins showed accumulations of synaptic proteins along axons and synaptic abnormalities. Taken together our results suggest that similar to the NGF-TrkA signaling endosome, a BMP signaling endosome that directly interacts with molecular motors likely exist. Thus problems in axonal transport occurs early, perturbs BMP signaling, and likely contributes to the synaptic abnormalities observed in these two diseases.
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Hansen
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Monique
authors.initials: M
authors.lastname: Mickiewicz
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Tadeusz J
authors.initials: TJ
authors.lastname: Kaczynski
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Samantha
authors.initials: S
authors.lastname: Fye
authors.affiliation: Department of Biological Sciences, The State University of New York at Buffalo, Buffalo, New York, United States of America.
authors.forename: Shermali
authors.initials: S
authors.lastname: Gunawardena
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D001370:Axonal Transport / Q000235:genetics / Q000502:physiology*; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism*; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016547:Kinesins / Q000235:genetics / Q000378:metabolism; D009046:Motor Neurons / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D016564:Amyloid beta-Protein Precursor; D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; C112506:MAD protein, Drosophila; D010455:Peptides; D014157:Transcription Factors; C097188:polyglutamine; C515209:Khc protein, Drosophila; D004398:Dyneins; D016547:Kinesins