Molecular mechanisms of severe congenital neutropenia (SCN) associated with deficiencies in vacuolar protein sorting homolog 45 (VPS45)

Frey, Laura (2022): Molecular mechanisms of severe congenital neutropenia (SCN) associated with deficiencies in vacuolar protein sorting homolog 45 (VPS45). Dissertation, LMU München: Fakultät für Biologie

Abstract

Vacuolar protein sorting 45 homolog (VPS45) is a member of the Sec1/Munc18 (SM) family and controls vesicle trafficking through the endosomal system. VPS45-deficient patients suffer from severe congenital neutropenia (SCN) and clinically manifest with bone marrow fibrosis as well as aberrant hematopoiesis. Furthermore, patients are refractory to the mainstay of treatment with granulocyte colony-stimulating factor (G-CSF). The molecular mechanisms underlying these diseases and the regulation of vesicular trafficking by VPS45 remain elusive. Thus, the overall goal of this thesis was to investigate the molecular mechanisms underlying VPS45 deficiencies. The data presented here reveal an essential role of VPS45 in maintaining the mor-phology and distribution of endosomal and lysosomal vesicles in human cells. Moreo-ver, it was shown that VPS45 is crucial for the efficient recycling of cargo proteins. Besides, the depletion of VPS45 results in disrupted endosome maturation. Conse-quently, cargos are trapped in early endosomes and prevented from efficient pro-cessing in the lysosomal compartment in the absence of VPS45. In this context, aber-rant trafficking of the G-CSF receptor (G-CSFR) was demonstrated in VPS45-deficient cells. Furthermore, a complete lack of VPS45 leads to embryonic death at an early stage in mice. Thus, this thesis identifies mammalian VPS45 as a crucial regulator of endosomal cargo transport and an essential protein during early embryogenesis of mice. It further deepens the understanding of VPS45-driven cellular processes in health and disease.

• Dokumententyp: Dissertationen (Dissertation, LMU München)
• Themengebiete: 500 Naturwissenschaften und Mathematik ; 500 Naturwissenschaften und Mathematik > 570 Biowissenschaften, Biologie
• Fakultäten: Fakultät für Biologie
• Sprache der Hochschulschrift: Englisch
• Datum der mündlichen Prüfung: 12. Januar 2022
• 1. Bericht­erstatter:in: Enard, Wolfgang