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Publication Abstract from PubMed

Prostate stem cell antigen (PSCA) is a Ly6/uPAR protein that targets neuronal nicotinic acetylcholine receptors (nAChRs). It exists in membrane-tethered and soluble forms, with the latter upregulated in Alzheimer's disease. We hypothesize that PSCA may be linked to a wider spectrum of neurological diseases and could induce neuroinflammation. Indeed, PSCA expression is significantly upregulated in the brain of patients with multiple sclerosis, Huntington's disease, Down syndrome, bipolar disorder, and HIV-associated dementia. To investigate PSCA's structure, pharmacology, and inflammatory function, we produced a correctly folded water-soluble recombinant analog (ws-PSCA). In primary hippocampal neurons and astrocytes, ws-PSCA differently regulates secretion of inflammatory factors and adhesion molecules and induces pro-inflammatory responses by increasing TNFbeta secretion. Heteronuclear NMR and (15)N relaxation measurements reveal a classical beta-structural three-finger fold with conformationally disordered loops II and III. Positive charge clustering on the molecular surface suggests the functional importance of ionic interactions by these loops. Electrophysiological studies in Xenopus oocytes point on ws-PSCA inhibition of alpha3beta2-, high-, and low-sensitive variants of alpha4beta2- (IC(50) ~50, 27, and 15 muM, respectively) but not alpha4beta4-nAChRs, suggesting targeting of the beta2 subunit. Ensemble docking and molecular dynamics simulations predict PSCA binding to high-sensitive alpha4beta2-nAChR at alpha4/beta2 and beta2/beta2 interfaces. Complexes are stabilized by ionic and hydrogen bonds between PSCA's loops II and III and the primary and complementary receptor subunits, including glycosyl groups. This study gives new structural and functional insights into PSCA's interaction with molecular targets and provides clues to understand its role in the brain function and mental disorders.

Pro-Inflammatory Protein PSCA Is Upregulated in Neurological Diseases and Targets beta2-Subunit-Containing nAChRs.,Shulepko MA, Che Y, Paramonov AS, Kocharovskaya MV, Kulbatskii DS, Ivanova AA, Chugunov AO, Bychkov ML, Kirichenko AV, Shenkarev ZO, Kirpichnikov MP, Lyukmanova EN Biomolecules. 2025 Sep 28;15(10):1381. doi: 10.3390/biom15101381. PMID:41154610^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.