PNMA2 forms non-enveloped virus-like capsids that trigger paraneoplastic neurological syndrome.

Autor:	Xu J; Department of Neurobiology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, UT, USA., Erlendsson S; The Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark., Singh M; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA., Regier M; Department of Neurobiology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, UT, USA., Ibiricu I; Max Planck Institute of Biochemistry, Martinsried, Germany., Day GS; Department of Neurology, Mayo Clinic, Jacksonville, FL, USA., Piquet AL; Department of Neurology, University of Colorado, Aurora, CO, USA., Clardy SL; Department of Neurology, Spencer Fox Eccles School of Medicine, University of Utah, and George E Wahlen VA Medical Center, Salt Lake City, UT, USA., Feschotte C; Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY, USA., Briggs JAG; The Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, UK.; Max Planck Institute of Biochemistry, Martinsried, Germany., Shepherd JD; Department of Neurobiology, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, UT, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Feb 09. Date of Electronic Publication: 2023 Feb 09.
DOI:	10.1101/2023.02.09.527862
Abstrakt:	The paraneoplastic Ma antigen ( PNMA ) genes are associated with cancer-induced paraneoplastic syndromes that present with neurological symptoms and autoantibody production. How PNMA proteins trigger a severe autoimmune disease is unclear. PNMA genes are predominately expressed in the central nervous system with little known functions but are ectopically expressed in some tumors. Here, we show that PNMA2 is derived from a Ty3 retrotransposon that encodes a protein which forms virus-like capsids released from cells as non-enveloped particles. Recombinant PNMA2 capsids injected into mice induce a robust autoimmune reaction with significant generation of autoantibodies that preferentially bind external "spike" PNMA2 capsid epitopes, while capsid-assembly-defective PNMA2 protein is not immunogenic. PNMA2 autoantibodies present in cerebrospinal fluid of patients with anti-Ma2 paraneoplastic neurologic disease show similar preferential binding to PNMA2 "spike" capsid epitopes. These observations suggest that PNMA2 capsids released from tumors trigger an autoimmune response that underlies Ma2 paraneoplastic neurological syndrome. Competing Interests: Competing interests C.F. is a consultant for Tessera Therapeutics, Inc. and HAYA Therapeutics, Inc. J.D.S is a co-founder of VNV, LLC and a consultant for Aera Therapeutics, Inc.
Databáze:	MEDLINE
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