Progress in the mechanism of neuronal surface P antigen modulating hippocampal function and implications for autoimmune brain disease. Issue 3 (June 2022)

• Record Type: Journal Article
• Authors: Barake, Francisca; Bravo-Zehnder, Marcela; González, Alfonso
• Is Part Of: Current opinion in neurology. Volume 35:Issue 3(2022)
• Page Start: 436
• Page End: 442
• Publication Date: 2022-06
• Subjects: antiribosomal P protein autoantibodies -- cognitive dysfunction -- glutamatergic synapsis -- neurogenesis -- N-Methyl-D-aspartic acid receptor -- PTPMEG/PTPN4 -- systemic lupus erythematosus -- ubiquitin proteasomal system; Neurology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.805
• DOI: 10.1097/WCO.0000000000001054
• Languages: English
• ISSNs: 1473-6551

Abstract

Abstract : Purpose of review: The aim of this study was to present a new regulation system in the hippocampus constituted by the neuronal surface P antigen (NSPA) and the tyrosine phosphatase PTPMEG/PTPN4, which provides mechanistic and therapeutic possibilities for cognitive dysfunction driven by antiribosomal P protein autoantibodies in patients with systemic lupus erythematosus (SLE). Recent findings: Mice models lacking the function of NSPA as an E3 ubiquitin ligase show impaired glutamatergic synaptic plasticity, decreased levels of NMDAR at the postsynaptic density in hippocampus and memory deficits. The levels of PTPMEG/PTPN4 are increased due to lower ubiquitination and proteasomal degradation, resulting in dephosphorylation of tyrosines that control endocytosis in GluN2 NMDAR subunits. Adult hippocampal neurogenesis (AHN) that normally contributes to memory processes is also defective in the absence of NSPA. Summary: NSPA function is crucial in memory processes controlling the stability of NMDAR at PSD through the ubiquitination of PTPMEG/PTPN4 and also through AHN. As anti-P autoantibodies reproduce the impairments of glutamatergic transmission, plasticity and memory performance seen in the absence of NSPA, it might be expected to perturb the NSPA/PTPMEG/PTPN4 pathway leading to hypofunction of NMDAR. This neuropathogenic mechanism contrasts with that of anti-NMDAR antibodies also involved in lupus cognitive dysfunction. Testing this hypothesis might open new therapeutic possibilities for cognitive dysfunction in SLE patients bearing anti-P autoantibodies.