Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG

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dc.contributor.authorEspinoza, Sofía
dc.contributor.authorBarake Sabbagh, M. Francisca
dc.contributor.authorCarvajal Cachaña, Francisco Javier
dc.contributor.authorSegovia Miranda, Fabián Josué
dc.contributor.authorCerpa Nebott, Waldo Francisco
dc.contributor.authorGonzález de la Rosa, Alfonso
dc.contributor.authorArredondo, Sebastián B.
dc.contributor.authorGuerrero, Fernanda G.
dc.contributor.authorValenzuela, David M.
dc.contributor.authorWyneken, Ursula
dc.date.accessioned2020-11-12T13:46:55Z
dc.date.available2020-11-12T13:46:55Z
dc.date.issued2020
dc.date.updated2020-11-08T01:09:13Z
dc.description.abstractAbstract Background Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. Results Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. Conclusions NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.
dc.identifier.citationBMC Biology. 2020 Nov 06;18(1):164
dc.identifier.doi10.1186/s12915-020-00877-2
dc.identifier.urihttps://doi.org/10.1186/s12915-020-00877-2
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/48233
dc.issue.numeroNo. 184
dc.language.isoen
dc.pagina.final17
dc.pagina.inicio1
dc.revistaBMC Biologyes_ES
dc.rights.holderThe Author(s)
dc.subjectNMDA receptores_ES
dc.subjectGluN2B Tyr1472es_ES
dc.subjectTyrosine phosphatase PTPMEG/PTPN4es_ES
dc.subjectSynaptic plasticityes_ES
dc.subjectMemoryes_ES
dc.subjectPostsynaptic densitieses_ES
dc.subjectUbiquitinationes_ES
dc.subjectNSPAes_ES
dc.subjectZZEF1es_ES
dc.subjectNPSLEes_ES
dc.subject.ddc573.8536
dc.subject.deweyBiologíaes_ES
dc.titleNeuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEGes_ES
dc.typeartículo
dc.volumenVol. 18
sipa.codpersvinculados141637
sipa.codpersvinculados237252
sipa.codpersvinculados1004561
sipa.codpersvinculados16584
sipa.codpersvinculados52306
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