Novel Interactive Partners of Neuroligin 3: New Aspects for Pathogenesis of Autism
- 986 Downloads
Autism is a neurodevelopmental disorder with a strong genetic predisposition. Neurolign 3 (NLGN3) as a postsynaptic transmembrane protein, functions in both neuron synaptogenesis and glia-neuron communications. Previously, a gain of function mutation (R451C) in NLGN3 was identified in autistic patients, which illustrates the involvement of NLGN3 in autism pathogenesis. As proper synaptic targeting and functioning are controlled by intracellular protein interactions, in the current study, we tried to discover the intracellular regulation network in which NLGN3 might be involved by a yeast two-hybrid-based interactor identification. Fifty-one protein candidate partners were identified after screening a human fetal complementary DNA (cDNA) library with an intracellular fragment of NLGN3. The interactions of NLGN3 with a subset of candidates, including EEF1A1, FLNA, ITPRIP, CYP11A1, MT-CO2, GPR175, ACOT2, and QPRT, were further validated in human neuroblastoma cells or brain tissues. Furthermore, our study suggested that NLGN3 was functioning in cytosolic calcium balance and participating in calcium-regulated cellular processes. Our findings of novel NLGN3 binding partners provide evidences of involvement of NLGN3 in multiple biological pathways, especially calcium regulating and mitochondrial function, thus suggesting further significance. This new data not only leads to a better understanding of the physiological functions of NLGN3, but also provide new aspects for pathogenesis of autism.
KeywordsNLGN3 Yeast two-hybrid Co-immunoprecipitation Protein-protein interaction Co-localization Cytosolic calcium
This work was supported in part by the “973” project (2012CB517905) of the Chinese Ministry of Sciences and technology, National Nature Science Foundation (30671157, 81301403), the Shanghai Municipal Department of Science and Technology (2009JC1412600), and the New York State Office of Mental Retardation and Developmental Disabilities (NYS OMRDD).
Conflict of Interest
The authors declare that there is no conflict of interests regarding the publication of this article.
- Avdjieva-Tzavella D, Mihailova S, Lukanov C, Naumova E, Simeonov E, Tincheva R, Toncheva D (2012) Mitochondrial DNA mutations in two Bulgarian children with autistic spectrum disorders. Balk J Med Genet 15(2):47–54Google Scholar
- Bourne Y, Marchot P (2014) The Neuroligins and their ligands: from structure to function at the synapse. J Mol NeurosciGoogle Scholar
- Gregory SG, Connelly JJ, Towers AJ, Johnson J, Biscocho D, Markunas CA, Lintas C, Abramson RK, Wright HH, Ellis P, Langford CF, Worley G, Delong GR, Murphy SK, Cuccaro ML, Persico A, Pericak-Vance MA (2009) Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med 7:62PubMedCentralPubMedCrossRefGoogle Scholar
- Hettinger JA, Liu X, Hudson ML, Lee A, Cohen IL, Michaelis RC, Schwartz CE, Lewis SM, Holden JJ (2012) DRD2 and PPP1R1B (DARPP-32) polymorphisms independently confer increased risk for autism spectrum disorders and additively predict affected status in male-only affected sib-pair families. Behav Brain Funct 8:19PubMedCentralPubMedCrossRefGoogle Scholar
- Janjetovic Z, Zmijewski MA, Tuckey RC, DeLeon DA, Nguyen MN, Pfeffer LM, Slominski AT (2009) 20-Hydroxycholecalciferol, product of vitamin D3 hydroxylation by P450scc, decreases NF-kappaB activity by increasing IkappaB alpha levels in human keratinocytes. PLoS One 4(6):e5988PubMedCentralPubMedCrossRefGoogle Scholar
- Kanibolotsky DS, Novosyl’na OV, Abbott CM, Negrutskii BS, El’skaya AV (2008) Multiple molecular dynamics simulation of the isoforms of human translation elongation factor 1A reveals reversible fluctuations between “open” and “closed” conformations and suggests specific for eEF1A1 affinity for Ca2+−calmodulin. BMC Struct Biol 8:4PubMedCentralPubMedCrossRefGoogle Scholar
- Martins-de-Souza D, Gattaz WF, Schmitt A, Maccarrone G, Hunyadi-Gulyás E, Eberlin MN, Souza GH, Marangoni S, Novello JC, Turck CW, Dias-Neto E (2009) Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia. J Psychiatr Res 43:978–986PubMedCrossRefGoogle Scholar
- Nakamura M, Sato K, Fukaya M, Araishi K, Aiba A, Kano M, Watanabe M (2004) Signaling complex formation of phospholipase Cbeta4 with metabotropic glutamate receptor type 1alpha and 1,4,5-trisphosphate receptor at the perisynapse and endoplasmic reticulum in the mouse brain. Eur J Neurosci 20(11):2929–2944PubMedCrossRefGoogle Scholar
- Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T, Zhang M, Paarmann I, Fuchs C, Harvey K, Jedlicka P, Schwarzacher SW, Betz H, Harvey RJ, Brose N, Zhang W, Varoqueaux F (2009) Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin. Neuron 63(5):628–642PubMedCrossRefGoogle Scholar
- Radyushkin K, Hammerschmidt K, Boretius S, Varoqueaux F, El-Kordi A, Ronnenberg A, Winter D, Frahm J, Fischer J, Brose N, Ehrenreich H (2009) Neuroligin-3-deficient mice: model of a monogenic heritable form of autism with an olfactory deficit. Genes Brain Behav 8(4):416–425PubMedCrossRefGoogle Scholar
- Valenti D, de Bari L, De Filippis B, Henrion-Caude A, Vacca RA (2014) Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: An overview of Down syndrome, autism, Fragile X and Rett syndrome. Neurosci Biobehav Rev. [Epub ahead of print]Google Scholar
- Zhang C, Milunsky JM, Newton S, Ko J, Zhao G, Maher TA, Tager-Flusberg H, Bolliger MF, Carter AS, Boucard AA, Powell CM, Südhof TC (2009) A neuroligin-4 missense mutation associated with autism impairs neuroligin-4 folding and endoplasmic reticulum export. J Neurosci 29(35):10843–10854PubMedCentralPubMedCrossRefGoogle Scholar