P1.33. SORCS2 SHAPES THE SECRETOME OF ASTROCYTES ACTIVATED AFTER ISCHEMIC STROKE.
Aleksandra Tempes1, Magda Bakun2, Karolina Czerny1, Sylwia Piątek1,3, Leif T. Koschützke3, Amido Daugardt3, Vatsalkumar Jariwala4, Kevin Joseph4, Christoph Harms3, Anna R. Malik1
1 University of Warsaw, Faculty of Biology, Cellular Neurobiology Research Group, Miecznikowa 1, Warsaw, Poland
2 Polish Academy of Sciences, Institute of Biochemistry and Biophysics, Warsaw, Poland
3 Charité-Universitätsmedizin Berlin, Department of Experimental Neurology, Berlin, Germany
4 Medical Center- University of Freiburg, Department of Neurosurgery, Laboratory for NeuroEngineering, Freiburg, Germany
INTRODUCTION: Ischemic stroke, caused by obstructed cerebral blood flow, results in neuronal death and astrocyte activation (astrogliosis). While current treatments focus on restoring circulation, increasing attention is directed toward the role of astrocytes in post-stroke brain repair, particularly in inflammation, glial scar formation, and extracellular matrix (ECM) remodeling. Transforming growth factor-beta (TGFβ), an immunomodulatory cytokine upregulated after stroke, potently activates astrocytes and modulates their secretory profile. Among the factors induced by TGFβ in astrocytes is SorCS2, a VPS10P domain receptor involved in intracellular protein sorting.
AIM(S): This study aims to investigate the role of SorCS2 in the TGFβ-dependent secretory activities of astrocytes, with a focus on ECM protein release and its implications for inflammation after ischemic stroke.
METHOD(S): We performed mass spectrometry-based analysis of secretomes from wild-type and SorCS2-knockout primary murine astrocytes treated with TGFβ. We employed the Middle Cerebral Artery Occlusion (MCAo) model in mice to assess in vivo effects of SorCS2 deficiency on ECM composition and immune cell morphology in post-stroke brain tissue.
RESULTS: Secretome profiling revealed that SorCS2-deficient astrocytes exhibited impaired secretion of key ECM molecules, including biglycan, agrin, neurocan, and thrombospondin-1 (Thbs1), in response to TGFβ. In vivo, SorCS2 knockout mice showed reduced levels of several ECM proteoglycans and displayed altered morphology of myeloid cells in the ischemic hemisphere compared to controls.
CONCLUSIONS: These findings suggest that SorCS2 is essential for ECM remodeling and inflammatory responses, providing insights into potential therapeutic targets for post-stroke therapeutic strategies.
FINANCIAL SUPPORT: This study was supported by the National Science Center, Poland 2020/37/B/NZ3/00761.