AB0169 Neuronal surface p antigen (NSPA), the cross-reacting target of lupus anti-ribosomal p autoantibodies, is a potential ubiquitin-ligase that regulates nmdar function
Authors: A. González, S. Espinoza, F. Segovia, F. Carvajal, W. Cerpa, U. Wyneken, P. Zamorano, A. Rojas, L. Massardo
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Anti-ribosomal P protein autoantibodies (anti-P) are found in 10%–15% of all patients with lupus<sup>1</sup> and their pathogenic role is supported by clinical studies showing association with psychosis<sup>2</sup> and cognitive deficit,<sup>3</sup> as well as by experiments in rodents showing depression like behaviour,<sup>4</sup> memory impairment<sup>5</sup> and electrophysiological alterations.<sup>6, 7</sup> The Neuronal Surface P Antigen (NSPA) identified as an anti-P cross-reacting protein<sup>8</sup> very likely mediates anti-P-driven brain diffuse dysfunctions through AMPAR and NMDAR synaptic transmission and plasticity.<sup>6</sup> <h3>Objectives</h3> To analyse molecular link between NSPA and NMDAR function involved in synaptic transmission and plasticity associated with memory, as a new approach to understand the neuropathogenic mechanism of anti-P antibodies. <h3>Methods</h3> Comparative studies in wild-type and NSPA knock-out mice on water maze performance (spatial memory), electrophysiology of CA3-CA1 glutamatergic transmission by field excitatory postsynaptic potential in hippocampal slices, biochemical analysis of synaptosomes and post-synaptic densities, including the mass and post-translational modifications (tyrosine phosphorylation and ubiquitylation) of relevant proteins. <h3>Results</h3> NSPA KO mice displayed the following alterations: 1) Impaired hippocampal-mediated spatial memory; 2) Decreased NMDAR-mediated glutamatergic transmission and long-term potentiation deficit, reflecting synaptic plasticity defects; 3) Selective lowered mass of GluN2A and GluN2B subunits of NMDAR in hippocampal synaptosomes and synaptic densities, accompanied by an enhanced mass and decreased ubiquitylation of the tyrosine phosphatase PTPN4 that interacts with NSPA and dephosphorylates the Tyr1472 of GluN2B of NMDAR. In addition, NSPA contains an APC-10 domain belonging to E3 ubiquitin ligases and a cotransfection assay in HEK293 cells demonstrated NSPA ubiquitylation as expected for these kinds of enzymes. <h3>Conclusions</h3> All together, these results suggest that NSPA is an ubiquitin ligase that having PTPN4 as a substrate regulates the tyrosine phosphorylation status and consequently the function of NMDAR at the synaptic region. <h3>References</h3> [1] Viana VT, Durcan L, Bonfa E, et al. Lupus2017;26:453–62. [2] Bonfa E, Golombek SJ, Kaufman LD, et al. N Engl J Med. 1987;317:265–71. [3] Massardo L, Bravo-Zehnder M, Calderon J, et al. Lupus. 2015;24:558–68. [4] Katzav A, Solodeev I, Brodsky O, et al. Arthritis Rheum. 2007;56:938–48. [5] Bravo-Zehnder M, Toledo EM, Segovia-Miranda F, et al. Arthritis &amp; Rheumatology2015;67:204–14. [6] Segovia-Miranda F, Serrano F, Dyrda A, et al. Arthritis Rheumatol. 2015;67:1598–610. [7] Gaburo N Jr., de Carvalho JF, Timo-Iaria CIM, et al. Lupus. 2017;26:463–9. [8] Matus S, Burgos PV, Bravo-Zehnder M, et al. J Exp Med. 2007;204:3221–34. <h3>Acknowledgements</h3> Financed by CONICYT Basal grant# PFB12/2007 and FONDECYT grant #1160513 <h3>Disclosure of Interest</h3> None declared