title: The N-ethylmaleimide-sensitive factor and dysbindin interact to modulate synaptic plasticity.
abstract: Dysbindin is a schizophrenia susceptibility factor and subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1) required for lysosome-related organelle biogenesis, and in neurons, synaptic vesicle assembly, neurotransmission, and plasticity. Protein networks, or interactomes, downstream of dysbindin/BLOC-1 remain partially explored despite their potential to illuminate neurodevelopmental disorder mechanisms. Here, we conducted a proteome-wide search for polypeptides whose cellular content is sensitive to dysbindin/BLOC-1 loss of function. We identified components of the vesicle fusion machinery as factors downregulated in dysbindin/BLOC-1 deficiency in neuroectodermal cells and iPSC-derived human neurons, among them the N-ethylmaleimide-sensitive factor (NSF). Human dysbindin/BLOC-1 coprecipitates with NSF and vice versa, and both proteins colocalized in a Drosophila model synapse. To test the hypothesis that NSF and dysbindin/BLOC-1 participate in a pathway-regulating synaptic function, we examined the role for NSF in dysbindin/BLOC-1-dependent synaptic homeostatic plasticity in Drosophila. As previously described, we found that mutations in dysbindin precluded homeostatic synaptic plasticity elicited by acute blockage of postsynaptic receptors. This dysbindin mutant phenotype is fully rescued by presynaptic expression of either dysbindin or Drosophila NSF. However, neither reduction of NSF alone or in combination with dysbindin haploinsufficiency impaired homeostatic synaptic plasticity. Our results demonstrate that dysbindin/BLOC-1 expression defects result in altered cellular content of proteins of the vesicle fusion apparatus and therefore influence synaptic plasticity.
authors.affiliation: Department of Cell Biology.
authors.forename: Avanti
authors.initials: A
authors.lastname: Gokhale
authors.affiliation: Department of Cell Biology.
authors.forename: Ariana P
authors.initials: AP
authors.lastname: Mullin
authors.affiliation: Department of Cell Biology.
authors.forename: Stephanie A
authors.identifier: http://orcid.org/0000-0003-0758-9500
authors.initials: SA
authors.lastname: Zlatic
authors.affiliation: Department of Cell Biology, Laboratory for Translational Cell Biology, and.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Easley
authors.affiliation: Department of Cell Biology, Laboratory for Translational Cell Biology, and.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Merritt
authors.affiliation: Department of Cell Biology, Laboratory for Translational Cell Biology, and.
authors.forename: Nisha
authors.initials: N
authors.lastname: Raj
authors.affiliation: Department of Biology, Agnes Scott College, Decatur, Georgia 30030.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Larimore
authors.affiliation: Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, United Kingdom, and.
authors.forename: David E
authors.initials: DE
authors.lastname: Gordon
authors.affiliation: Department of Biomedical Science, The University of Sheffield, Sheffield S10 2TN, United Kingdom, and.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Peden
authors.affiliation: Biogen, Cambridge, Massachusetts 02493 subhabrata.sanyal@biogenidec.com vfaunde@emory.edu.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Sanyal
authors.affiliation: Department of Cell Biology, Center for Social Translational Neuroscience, Emory University, Atlanta, Georgia 30322, subhabrata.sanyal@biogenidec.com vfaunde@emory.edu.
authors.forename: Victor
authors.initials: V
authors.lastname: Faundez
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D045744:Cell Line, Tumor; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008545:Melanoma / Q000473:pathology; D052066:N-Ethylmaleimide-Sensitive Proteins / Q000235:genetics / Q000378:metabolism*; D009415:Nerve Net / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009469:Neuromuscular Junction / Q000235:genetics / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D050600:SNARE Proteins / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D013572:Synaptic Vesicles / Q000235:genetics / Q000378:metabolism
chemical_list: C104378:BLOC1S1 protein, human; D029721:Drosophila Proteins; C569104:Dysb protein, Drosophila; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; D052066:N-Ethylmaleimide-Sensitive Proteins
keywords: BLOC-1; DTNBP1; NSF; SILAC; dysbindin; schizophrenia