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

Content Provider	Springer Nature : BioMed Central
Author	Espinoza, Sofía Arredondo, Sebastián B. Barake, Francisca Carvajal, Francisco Guerrero, Fernanda G. Segovia-Miranda, Fabian Valenzuela, David M. Wyneken, Ursula Rojas-Fernández, Alejandro Cerpa, Waldo Massardo, Loreto Varela-Nallar, Lorena González, Alfonso
Abstract	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.
Related Links	https://bmcbiol.biomedcentral.com/counter/pdf/10.1186/s12915-020-00877-2.pdf
Ending Page	17
Page Count	17
Starting Page	1
File Format	HTM / HTML
ISSN	17417007
DOI	10.1186/s12915-020-00877-2
Journal	BMC Biology
Issue Number	1
Volume Number	18
Language	English
Publisher	BioMed Central
Publisher Date	2020-11-06
Access Restriction	Open
Subject Keyword	Life Sciences ZZEF1 NMDA receptor GluN2B Tyr1472 Tyrosine phosphatase PTPMEG/PTPN4 Synaptic plasticity Memory Postsynaptic densities Ubiquitination NSPA NPSLE
Content Type	Text
Resource Type	Article
Subject	Ecology, Evolution, Behavior and Systematics Structural Biology Biochemistry, Genetics and Molecular Biology Plant Science Biotechnology Physiology Agricultural and Biological Sciences Cell Biology Developmental Biology
Journal Impact Factor	4.4/2023
5-Year Journal Impact Factor	5.4/2023

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