Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

Yalçın, Belgin; Zhao, Lu; Stofanko, Martin; O’Sullivan, Niamh C.; Kang, Zi Han; Roost, Annika; Thomas, M.; Zaessinger, Sophie; Blard, Olivier; Patto, Alex L; Sohail, Anood; Baena, Valentina; Terasaki, Mark; O’Kane, Cahir J.

doi:10.7554/elife.23882

Cited by 67 publications

(82 citation statements)

References 68 publications

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“…Atlastin has been shown to physically interact directly or indirectly with several proteins in the ER membrane, including reticulons, REEPs, spastin, and lunapark (6,7,17,25,37). Given the structural nature of the REEP/reticulon family (24,38,39) and the relatively large abundance of these proteins, the most likely interactions with atlastin that may regulate function are with the reticulons. To examine a potential regulatory role of reticulon, we analyzed the effects of Rtnl1 in dAtl-mediated in vitro fusion.…”

Section: Co-reconstitution Of Reticulon With Atlastin Does Not Influementioning

confidence: 99%

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

Betancourt-Solis

Desai²,

McNew

2018

Journal of Biological Chemistry

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The endoplasmic reticulum (ER) is composed of flattened sheets and interconnected tubules that extend throughout the cytosol and makes physical contact with all other cytoplasmic organelles. This cytoplasmic distribution requires continuous remodeling. These discrete ER morphologies require specialized proteins that drive and maintain membrane curvature. The GTPase atlastin is required for homotypic fusion of ER tubules. All atlastin homologs possess a conserved domain architecture consisting of a GTPase domain, a three-helix bundle middle domain, a hydrophobic membrane anchor, and a C-terminal cytosolic tail. Here, we examined several Drosophila-human atlastin chimeras to identify functional domains of human atlastin-1 in vitro. Although all chimeras could hydrolyze GTP, only chimeras containing the human C-terminal tail, hydrophobic segments, or both could fuse membranes in vitro. We also determined that co-reconstitution of atlastin with reticulon does not influence GTPase activity or membrane fusion. Finally, we found that both human and Drosophila atlastin hydrophobic membrane anchors do not span the membrane, but rather form two intramembrane hairpin loops. The topology of these hairpins remains static during membrane fusion and does not appear to play an active role in lipid mixing.

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Section: Co-reconstitution Of Reticulon With Atlastin Does Not Influementioning

confidence: 99%

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

Betancourt-Solis

Desai²,

McNew

2018

Journal of Biological Chemistry

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“…It typically comprises more than half of the total animal cell membranes (Alberts et al, 2002), or 35% of cytoplasmic volume at any one time (Valm et al, 2017). Light and electron microscopy (EM), and membrane dye labeling, suggest that uniquely among organelles, the ER appears pervasive and continuous throughout cells, including neurons (Tsukita and Ishikawa, 1976;Terasaki et al, 1994;Wu et al, 2017;Yalçın et al, 2017) (Figure 1). Physically connected to the nuclear envelope, and sharing with it a common lumen, ER includes rough and smooth ER domains.…”

Section: Introductionmentioning

confidence: 99%

“…Until recently, axonal ER received scant attention since its characterization by electron microscopy some four decades ago e.g., Tsukita and Ishikawa (1976), partly due to the lack of molecular markers and the difficulty of resolving it using conventional osmium staining in thin EM sections. However, both these hurdles have recently been overcome e.g., Villegas et al (2014) and Yalçın et al (2017). Axonal ER has the characteristics of a largely smooth tubular ER network, which must share many of its functions with the better characterized equivalent network in non-neuronal cells, but with specialized roles and constraints that reflect the long and narrow dimensions of axons.…”

Section: Introductionmentioning

confidence: 99%

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

2020

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The physical continuity of axons over long cellular distances poses challenges for their maintenance. One organelle that faces this challenge is endoplasmic reticulum (ER); unlike other intracellular organelles, this forms a physically continuous network throughout the cell, with a single membrane and a single lumen. In axons, ER is mainly smooth, forming a tubular network with occasional sheets or cisternae and low amounts of rough ER. It has many potential roles: lipid biosynthesis, glucose homeostasis, a Ca 2+ store, protein export, and contacting and regulating other organelles. This tubular network structure is determined by ER-shaping proteins, mutations in some of which are causative for neurodegenerative disorders such as hereditary spastic paraplegia (HSP). While axonal ER shares many features with the tubular ER network in other contexts, these features must be adapted to the long and narrow dimensions of axons. ER appears to be physically continuous throughout axons, over distances that are enormous on a subcellular scale. It is therefore a potential channel for long-distance or regional communication within neurons, independent of action potentials or physical transport of cargos, but involving its physiological roles such as Ca 2+ or organelle homeostasis. Despite its apparent stability, axonal ER is highly dynamic, showing features like anterograde and retrograde transport, potentially reflecting continuous fusion and breakage of the network. Here we discuss the transport processes that must contribute to this dynamic behavior of ER. We also discuss the model that these processes underpin a homeostatic process that ensures both enough ER to maintain continuity of the network and repair breaks in it, but not too much ER that might disrupt local cellular physiology. Finally, we discuss how failure of ER organization in axons could lead to axon degenerative diseases, and how a requirement for ER continuity could make distal axons most susceptible to degeneration in conditions that disrupt ER continuity.

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“…The axonal ER is a network of tubules which are highly dynamic and exist as a continuous network throughout the axon (Öztürk, O'Kane and Pérez-Moreno, 2020). This ER tubule continuity is required for axonal integrity and survival (Yalçın et al, 2017) and for interaction with microtubules during development to control axon polarity and growth (Farias, 2019). The involvement of the ER in axon regeneration has not been extensively studied in mammalian CNS neurons before.…”

Section: Discussionmentioning

confidence: 99%

“…The ER exists as a continuous tubular organelle through axons (similar to an axon within the axon), and its genetic disruption causes axonal degeneration (Yalçın et al, 2017). Reestablishment of the axonal ER may be equally as important as the re-establishment of the axon membrane for successful regeneration.…”

Section: Protrudin Promotes Regeneration Through Interaction With Thementioning

confidence: 99%

Protrudin functions as a scaffold in the endoplasmic reticulum to support axon regeneration in the adult central nervous system

Petrova

Tribble

et al. 2020

Preprint

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Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin's endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing 2 important roles for these cellular components in mediating regeneration in the adult central nervous system.

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Modeling of axonal endoplasmic reticulum network by spastic paraplegia proteins

Cited by 67 publications

References 68 publications

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

The atlastin membrane anchor forms an intramembrane hairpin that does not span the phospholipid bilayer

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

Protrudin functions as a scaffold in the endoplasmic reticulum to support axon regeneration in the adult central nervous system

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