Tyro3 and Gas6 are associated with white matter and myelin integrity in multiple sclerosis.

Background: The Gas6/TAM (Tyro3, Axl, and Mer) receptor system has been implicated in demyelination and delayed remyelination in experimental animal models, but data in humans are scarce. We aimed to investigate the role of Gas6/TAM in neurodegenerative processes in multiple sclerosis (MS).
Methods: From a prospective 5-year follow-up study, soluble Gas6/TAM biomarkers were analyzed in cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA) at baseline in patients with relapsing-remitting MS (RRMS) (n = 40), progressive MS (PMS) (n = 20), and healthy controls (HC) (n = 25). Brain volumes, including myelin content (MyC) and white matter (WM) were measured by synthetic magnetic resonance imaging at baseline, 12 months, and 60-month follow-up. Associations with brain volume changes were investigated in multivariable linear regression models. Gas6/TAM concentrations were also determined at 12 months follow-up in RRMS to assess treatment response.
Results: Baseline concentrations of Tyro3, Axl, and Gas6 were significantly higher in PMS vs. RRMS and HC. Mer was higher in PMS vs. HC. Tyro3 and Gas6 were associated with reduced WM (β = 25.5, 95% confidence interval [CI] [6.11-44.96, p = 0.012; β = 11.4, 95% CI [0.42-22.4], p = 0.042, respectively) and MyC (β = 7.95, 95%CI [1.84-14.07], p = 0.012; β = 4.4, 95%CI [1.04-7.75], p = 0.012 respectively) at 60 months. Patients with evidence of remyelination at last follow-up had lower baseline soluble Tyro3 (p = 0.033) and Gas6 (p = 0.014). Except Mer, Gas6/TAM concentrations did not change with treatment in RRMS.
Discussion: Our data indicate a potential role for the Gas6/TAM receptor system in neurodegenerative processes influencing demyelination and ineffective remyelination.
Competing Interests: Declarations. Competing interests: IR has received compensation for lectures from Biogen, Novartis, Merck, and Sanofi, and has served on advisory boards for Sanofi; LN has received lecture honoraria from Biogen, Novartis, Teva, Sanofi and has served on advisory boards for Merck, Janssen and Sanofi; HKhas nothing to declare; AN has nothing to declare; SR has nothing to declare; ERhas nothing to declare; SShas received compensation for lectures and/or advisory board membership from Merck and Novartis;CM has served at scientific advisory boards and/or held lectures for Biogen, Merck, Novartis, Roche, Sanofi. Serves as board member for Alzinova AB, Sweden; MA has received compensation for lectures and/or advisory boards from Biogen, Genzyme, and Novartis; SFhas nothing to declare;  KB served as a consultant and at advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper; HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work); JLhas received travel support and/or lecture honoraria and has served on scientific advisory boards for Alexion, Almirall, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche and Sanofi; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator initiated study.
(© 2024. The Author(s).)