Simone Hjæresen1,2, Tobias Sejbaek3,4, Marcus Axelsson5, Helle Vinsløv-Jensen1, Sif Kløvedal Mortensen1, Gorm Pihl-Jensen6, Lenka Novakova5, Julie Damgaard Rosgaard Christensen1, Christian Bonde Pedersen7,2, Bo Halle7,2, Frantz Rom Poulsen7,2, Jette Lautrup Frederiksen6, Mengliang Zhang1,2, Eirikur Benedikz8, Jan Lycke5, Zsolt Illes1,9,2, Åsa Fex Svenningsen10,11. 1. Department of Molecular Medicine- Neurobiology Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000, Odense, Denmark. 2. University of Southern Denmark, BRIDGE, University of Southern Denmark, Odense, Denmark. 3. Department of Regional Health Research, University of Southern Denmark, 5000, Odense, Denmark. 4. Department of Neurology, Southwest Jutland University Hospital, 6700, Esbjerg, Denmark. 5. Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy, and Department of Neurology, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. 6. Department of Neurology, University of Copenhagen, Rigshospitalet Glostrup, Copenhagen, Denmark. 7. Department of Neurosurgery, Clinical Institute, University of Southern Denmark, Odense University Hospital, Odense, Denmark. 8. Faculty of Health Sciences, University of Southern Denmark, J.B. Winsløws Vej 21, 5000, Odense, Denmark. 9. Department of Neurology, University of Southern Denmark, Odense University Hospital, Odense, Denmark. 10. Department of Molecular Medicine- Neurobiology Research, University of Southern Denmark, J.B. Winsløws Vej 21, 5000, Odense, Denmark. aasvenningsen@health.sdu.dk. 11. University of Southern Denmark, BRIDGE, University of Southern Denmark, Odense, Denmark. aasvenningsen@health.sdu.dk.
Abstract
BACKGROUND: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. OBJECTIVE: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. METHODS: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. RESULTS: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. CONCLUSION: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.
BACKGROUND: High Temperature Requirement Serine Protease A1 (HTRA1) degrades extracellular matrix molecules (ECMs) and growth factors. It interacts with several proteins implicated in multiple sclerosis (MS), but has not previously been linked to the disease. OBJECTIVE: Investigate the levels of HTRA1 in cerebrospinal fluid (CSF) in different subtypes of MS and brain tissue. METHODS: Using ELISA, HTRA1 levels were compared in CSF from untreated patients with relapsing-remitting MS (RRMS, n = 23), secondary progressive MS (SPMS, n = 26) and healthy controls (HCs, n = 26). The effect of disease modifying therapies (DMTs) were examined in both patient groups. Cellular distribution in human brain was studied using immunochemistry and the oligointernode database, based on a single-nuclei RNA expression map. RESULTS: HTRA1 increased in RRMS and SPMS compared to HCs. DMT decreased HTRA1 levels in both types of MS. Using ROC analysis, HTRA1 cut-offs could discriminate HCs from RRMS patients with 100% specificity and 82.6% sensitivity. In the brain, HTRA1 was expressed in glia and neurons. CONCLUSION: HTRA1 is a promising CSF biomarker for MS correlating with disease- and disability progression. Most cell species of the normal and diseased CNS express HTRA1 and the expression pattern could reflect pathological processes involved in MS pathogenesis.