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Complete Dissertation VU Research Portal The endolysosomal system in neuronal physiology and pathology Vazquez Sanchez, S. 2019 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) Vazquez Sanchez, S. (2019). The endolysosomal system in neuronal physiology and pathology. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 05. Oct. 2021 The endolysosomal system in neuronal physiology and pathology Sonia Vazquez Sanchez Printed by: Ipskamp Layout by: Sonia Vazquez Sanchez Cover: Confocal microscopy image of a human neuron overexpressing TauP301L-GFP (green) and treated with tau fibrils. Compartments of the endolysosomal system are immunolabelled in red (CD63) and in yellow (LAMP1). The nucleus (DAPI) and the dendrites (MAP2) are labelled in blue. The bookmark shows a zoom of this neuron acquired with STED microscopy. The publication of this thesis was financially supported by CNCR and Alzheimer Nederland. © 2019 by Sonia Vazquez Sanchez ISBN: 978-94-028-1522-1 VRIJE UNIVERSITEIT THE ENDOLYSOSOMAL SYSTEM IN NEURONAL PHYSIOLOGY AND PATHOLOGY ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der der Bètawetenschappen op maandag 17 juni 2019 om 15.45 uur in de aula van de universiteit, De Boelelaan 1105 door Sonia Vazquez Sanchez geboren te Madrid, Spanje promotor: prof.dr. M.Verhage copromotor: dr. J.R.T. van Weering CONTENTS Chapter 1 7 General introduction Chapter 2 29 VPS35 depletion does not impair presynaptic structure and function Chapter 3 57 Sorting nexin 4 is an endosomal sorting protein located to synapses Chapter 4 105 The seeding of tau pathology alters the endolysosomal system Chapter 5 135 Summary, general discussion, and future directions Chapter 1 General introduction 7 Chapter 1 THE ENDOLYSOSOMAL SYSTEM The endolysosomal system consists of a complex network of interconnected membrane compartments with constant flux of material. The appearance of an endomembrane trafficking system was a key event in evolution for the prokaryote-to-eukaryote transition (see review (Dacks and Field, 2007)). The evolution of this trafficking system has been critical for the emergence and diversification of complex cell types such as neurons, and organisms such as humans. For example, it is required for neuronal development and function, mediating cell fate decisions, cell migration, axon outgrowth and polarity (see review (Yap and Winckler, 2012)). The endolysosomal system maintains cell homeostasis by cargo sorting, degradation and recycling. Different endolysosomal compartments are distinguished based on their function, molecular composition and structure (Figure 1 and Table 1). This distinction between compartments is very useful to study the endolysosomal system; however, it is important to note that they are not fixed and separate entities. Instead, they are extremely dynamic with constant exchange of material and with highly overlapping features. Both the endolysosomal molecular machinery and ultrastructure are used to define endolysosomal compartments (Table 1). Rab proteins are widely used as organelle markers, including different endolysosomal compartments. Rab proteins are a family of small monomeric GTPases part of the RAS superfamily which regulate membrane trafficking by recruiting effector proteins in a GTP-bound conformation (see review (Stenmark, 2009)). On the early endosome, Rab4 and Rab5 mediate early endosomal fusion and biogenesis. On recycling endosomes, Rab11 is involved in trafficking cargo to the plasma membrane. On late endosomal compartments, Rab7 is involved in endosomal maturation, lysosome biogenesis and trafficking cargo away from the late endosome (see review (Galvez et al., 2012)). Phosphoinositides are phosphorylated forms of phosphatidylinositol (PI) that are also differently distributed on the endolysosomal membranes and regulate membrane trafficking. PI(3)P is enriched on early endosome membranes, while PI(4)P is on recycling endosomes and PI(3,5)P2 on late endosomes. In the lysosomal membrane, several phosphoinositides coexist including PI(3)P, PI(4) P, and PI(4,5)P2 (see review (Wallroth and Haucke, 2018)). Other transmembrane or membrane associated proteins are frequently used to label the different endolysosomal compartments. For example, early endosome antigen 1 (EEA1) is used to label early endosomes because it localizes to early endosomal membranes to mediate endosome docking and fusion (Christoforidis et al., 1999a). Tetraspanin CD63 is used to label late endosomes/multivesicular bodies (MVBs) because it is highly enriched on intraluminal vesicles (ILVs) in MVB (see review (Pols and Klumperman, 2009)). For lysosomes, there are mainly three transmembrane proteins used as molecular markers due to their 8 General introduction Endoplasmic Nucleus reticulum 1 Golgi apparatus Lysosome trans-Golgi network MVB Early Endolysosome endosome Endocytic Recycling vesicle endosome Plasma membrane Exosomes Extracellular space Figure 1: Simplified schema of the main endolysosomal compartments and pathways: biosynthesis (purple arrows), recycling (green arrows) and degradation (blue arrows). Cargo (black dot) is defined as transmembrane proteins, their lipids and associated proteins. In the biosynthetic pathway, membrane proteins are synthesized on the endoplasmic reticulum, transported and modified at the Golgi apparatus, and sorted in the trans-Golgi network (purple arrows). In the retrograde pathway, endocytic vesicles from the plasma membrane fuse with early endosomes, where the fate of the cargo is determined: the endocytic cargo will be degraded or recycled. If the cargo is recycled, it will be sorted in membrane tubules which emanate from the endosome to other cell compartments such as the trans-Golgi network, the recycling endosome or directly to the plasma membrane. If the cargo is degraded, it will be included in the intraluminal vesicles inside the early endosome which accumulate during the process of maturation to late endosome. The late endosome or multivesicular body (MVB) fuses with the lysosome forming a hybrid organelle called endolysosome, in which degradation takes place. After that, the endolysosome can mature to a lysosome. Alternatively, the multivesicular body can fuse with the plasma membrane to release its content (black arrow). When the intraluminal vesicles are release to the extracellular space, they are called exosomes. 9 Chapter 1 predominantly lysosomal membrane localization: the lysosome-associated membrane protein 1 (LAMP1), involved in lysosomal stability, integrity and exocytosis (see review (Saftig and Klumperman, 2009)), the lysosome-associated membrane protein 2 (LAMP2), involved in chaperone-mediated autophagy (see review (Saftig and Klumperman, 2009)) and the lysosomal integral membrane protein 2 (LIMP2) which is a receptor for lysosomal transport of the acid hydrolase β-glucocerebrosidase (GC) (see review (Gonzalez et al., 2014)). Other molecules used to define endolysosomes are based on their function such as DQTM Red-BSA which produces a bright fluorescent product when it is hydrolyzed (Bright et al., 2016). An alternative approach to discern between distinct endosolysosomal compartments is the ultrastructural analysis by transmission electron microscopy (TEM), which provides the high resolution required to resolve the complex membrane structure of the endolysosomal system (see Table1 and review (Klumperman and Raposo, 2014)). 1 General sorting mechanism and machineries The biosynthetic and retrograde pathway converge in the early endosome. The early endosomes constitute a sorting station in which cargo is sorted for degradation or retrieved to be targeted to a different location. To assure specificity in cargo sorting, the endosolysosomal system faces two main challenges: recognizing the fate of each cargo and separating it from neighboring cargo that needs to be trafficked by a distinct pathway. This specificity is achieved through the coordinated action of proteins, which can be viewed as molecular machineries constituted by protein sub-complexes. Here, we will review the general endosomal sorting principles using the retromer-mediated sorting machinery as an example. Other protein sub-complexes follow similar principles including retriever-mediated sorting or ESCRT sorting (see Figure 4) (see review (McNally and Cullen, 2018)). Briefly, in the early endosomal membrane there is both cargo which needs to be recycled and which needs to be degraded. Cargos contain a sorting signal which is recognized by cargo-recognition
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