Abstract
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 Ca2+ 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 Ca2+ 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.
Highlights
Endoplasmic reticulum (ER) is a membrane-bound organelle found throughout the cytoplasm of all eukaryotic cells
The Vps13 family of lipid-transfer proteins are localized to a variety of intracellular membrane contacts; of these, Vps13A, which directly interacts with VAPA (Yeshaw et al, 2019), is found at mammalian ER-mitochondrial membrane contact sites (MCSs) (Kumar N. et al, 2018), it is not known how much it contributes to lipid transport there (Petrungaro and Kornmann, 2019)
Since the axonal ER network is dynamic, since the ER assembly mechanisms appear to be quite efficient at maintaining a continuous network and avoiding gaps even when ER tubule numbers are significantly reduced, and since there appear to be no physical constraints on an even denser network of ER tubules (Yalçın et al, 2017), we suggest the existence of homeostatic mechanisms to achieve the physiological density and continuity of ER tubules
Summary
Endoplasmic reticulum (ER) is a membrane-bound organelle found throughout the cytoplasm of all eukaryotic cells. KD: decreased synaptic activity (Gómez-Suaga et al, 2019) ∗KD: ER discontinuity, impaired ER tubules dynamics, and decreased presynaptic Ca2+ influx and synaptic vesicle cycling (Lindhout et al, 2019) ∗LOF: impaired axonal localization of Dscam cell surface receptors (Yang et al, 2012); decreased number and increased size of presynaptic terminals, and impaired presynaptic MT network (Pennetta et al, 2002); decreased presynaptic BMP signaling (Ratnaparkhi et al, 2008) *OE: increased number and decreased size of presynaptic terminals (Pennetta et al, 2002); decreased presynaptic active zones (Ratnaparkhi et al, 2008) KD: neurite degeneration (Park et al, 2015)
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