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

Sofía Espinoza; Sebastián B. Arredondo; Francisca Barake; Francisco Carvajal; Fernanda G. Guerrero; Fabian Segovia-Miranda; David M. Valenzuela; Úrsula Wyneken; Alejandro Rojas-Fernández; Waldo Cerpa; Loreto Massardo; Lorena Varela-Nallar; Alfonso González

doi:10.1186/s12915-020-00877-2

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

Sofía Espinoza, Sebastián B. Arredondo, Francisca Barake, Francisco Carvajal, Fernanda G. Guerrero, Fabian Segovia-Miranda, David M. Valenzuela, Úrsula Wyneken, Alejandro Rojas-Fernández, Waldo Cerpa, Loreto Massardo, Lorena Varela-Nallar, Alfonso González^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English
Article number	164
Journal	BMC Biology
Volume	18
Issue number	1
DOIs	https://doi.org/10.1186/s12915-020-00877-2
State	Published - 1 Dec 2020

Bibliographical note

Funding Information:
The authors acknowledge the services provided by UC CINBIOT Animal Facility funded by PIA CONICYT Program for Associative Research, of the Chilean National Council for Science and Technology ECM-07.

Funding Information:
This work received financial support from the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) “Programa de Apoyo a Centros con Financiamiento Basal” AFB170005 to the Center for Aging and Regeneration (CARE) (A.G. and W.C.) and AFB170004 to Fundación Ciencia & Vida (A.G. and F.B.); Fondo Nacional de Desarrollo Científico y Tecnológico (Fondecyt) grant No1160513 (L.M.), Fondecyt grant No1190620, Sociedad Química y Minera de Chile (SQM) for special grant “the role of lithium in human health and disease”; BMBF 20150065 (PCI) (W.C.); Fondecyt grant No1190461 (L.V.N.); Fondecyt grant No1140108 (U.W.); and FONDEF IdeA ID17I10037 (A.R.F). Doctoral fellowships from CONICYT (S.E., F.C., S.B.A. and F.B.). Acknowledgements

Publisher Copyright:
© 2020, The Author(s).

Keywords

GluN2B Tyr1472
Memory
NMDA receptor
NPSLE
NSPA
Postsynaptic densities
Synaptic plasticity
Tyrosine phosphatase PTPMEG/PTPN4
Ubiquitination
ZZEF1

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Espinoza, S., Arredondo, S. B., Barake, F., Carvajal, F., Guerrero, F. G., Segovia-Miranda, F., Valenzuela, D. M., Wyneken, Ú., Rojas-Fernández, A., Cerpa, W., Massardo, L., Varela-Nallar, L., & González, A. (2020). Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG. BMC Biology, 18(1), Article 164. https://doi.org/10.1186/s12915-020-00877-2

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

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.",

keywords = "GluN2B Tyr1472, Memory, NMDA receptor, NPSLE, NSPA, Postsynaptic densities, Synaptic plasticity, Tyrosine phosphatase PTPMEG/PTPN4, Ubiquitination, ZZEF1, GluN2B Tyr1472, Memory, NMDA receptor, NPSLE, NSPA, Postsynaptic densities, Synaptic plasticity, Tyrosine phosphatase PTPMEG/PTPN4, Ubiquitination, ZZEF1",

author = "Sof{\'i}a Espinoza and Arredondo, {Sebasti{\'a}n B.} and Francisca Barake and Francisco Carvajal and Guerrero, {Fernanda G.} and Fabian Segovia-Miranda and Valenzuela, {David M.} and {\'U}rsula Wyneken and Alejandro Rojas-Fern{\'a}ndez and Waldo Cerpa and Loreto Massardo and Lorena Varela-Nallar and Alfonso Gonz{\'a}lez",

note = "Funding Information: The authors acknowledge the services provided by UC CINBIOT Animal Facility funded by PIA CONICYT Program for Associative Research, of the Chilean National Council for Science and Technology ECM-07. Funding Information: This work received financial support from the Comisi{\'o}n Nacional de Investigaci{\'o}n Cient{\'i}fica y Tecnol{\'o}gica (CONICYT) “Programa de Apoyo a Centros con Financiamiento Basal” AFB170005 to the Center for Aging and Regeneration (CARE) (A.G. and W.C.) and AFB170004 to Fundaci{\'o}n Ciencia & Vida (A.G. and F.B.); Fondo Nacional de Desarrollo Cient{\'i}fico y Tecnol{\'o}gico (Fondecyt) grant No1160513 (L.M.), Fondecyt grant No1190620, Sociedad Qu{\'i}mica y Minera de Chile (SQM) for special grant “the role of lithium in human health and disease”; BMBF 20150065 (PCI) (W.C.); Fondecyt grant No1190461 (L.V.N.); Fondecyt grant No1140108 (U.W.); and FONDEF IdeA ID17I10037 (A.R.F). Doctoral fellowships from CONICYT (S.E., F.C., S.B.A. and F.B.). Acknowledgements Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

day = "1",

doi = "10.1186/s12915-020-00877-2",

language = "English",

volume = "18",

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Espinoza, S, Arredondo, SB, Barake, F, Carvajal, F, Guerrero, FG, Segovia-Miranda, F, Valenzuela, DM, Wyneken, Ú, Rojas-Fernández, A, Cerpa, W, Massardo, L, Varela-Nallar, L & González, A 2020, 'Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG', BMC Biology, vol. 18, no. 1, 164. https://doi.org/10.1186/s12915-020-00877-2

TY - JOUR

T1 - Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG

AU - Espinoza, Sofía

AU - Arredondo, Sebastián B.

AU - Barake, Francisca

AU - Carvajal, Francisco

AU - Guerrero, Fernanda G.

AU - Segovia-Miranda, Fabian

AU - Valenzuela, David M.

AU - Wyneken, Úrsula

AU - Rojas-Fernández, Alejandro

AU - Cerpa, Waldo

AU - Massardo, Loreto

AU - Varela-Nallar, Lorena

AU - González, Alfonso

N1 - Funding Information: The authors acknowledge the services provided by UC CINBIOT Animal Facility funded by PIA CONICYT Program for Associative Research, of the Chilean National Council for Science and Technology ECM-07. Funding Information: This work received financial support from the Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) “Programa de Apoyo a Centros con Financiamiento Basal” AFB170005 to the Center for Aging and Regeneration (CARE) (A.G. and W.C.) and AFB170004 to Fundación Ciencia & Vida (A.G. and F.B.); Fondo Nacional de Desarrollo Científico y Tecnológico (Fondecyt) grant No1160513 (L.M.), Fondecyt grant No1190620, Sociedad Química y Minera de Chile (SQM) for special grant “the role of lithium in human health and disease”; BMBF 20150065 (PCI) (W.C.); Fondecyt grant No1190461 (L.V.N.); Fondecyt grant No1140108 (U.W.); and FONDEF IdeA ID17I10037 (A.R.F). Doctoral fellowships from CONICYT (S.E., F.C., S.B.A. and F.B.). Acknowledgements Publisher Copyright: © 2020, The Author(s).

PY - 2020/12/1

Y1 - 2020/12/1

N2 - 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.

AB - 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.

KW - GluN2B Tyr1472

KW - Memory

KW - NMDA receptor

KW - NPSLE

KW - NSPA

KW - Postsynaptic densities

KW - Synaptic plasticity

KW - Tyrosine phosphatase PTPMEG/PTPN4

KW - Ubiquitination

KW - ZZEF1

KW - GluN2B Tyr1472

KW - Memory

KW - NMDA receptor

KW - NPSLE

KW - NSPA

KW - Postsynaptic densities

KW - Synaptic plasticity

KW - Tyrosine phosphatase PTPMEG/PTPN4

KW - Ubiquitination

KW - ZZEF1

UR - http://www.scopus.com/inward/record.url?scp=85095428512&partnerID=8YFLogxK

U2 - 10.1186/s12915-020-00877-2

DO - 10.1186/s12915-020-00877-2

M3 - Article

C2 - 33158444

AN - SCOPUS:85095428512

SN - 1741-7007

VL - 18

JO - BMC Biology

JF - BMC Biology

IS - 1

M1 - 164

ER -

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

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Keywords

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