Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration

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.

Keywords: axonal transport; calcium stores; endoplasmic reticulum; hereditary spastic paraplegia; neurodegeneration; organelle contact sites; smooth ER.

FIGURE 1

Endoplasmic reticulum (ER) distribution in neuronal cells. (A) ER network (blue) is continuously distributed throughout the cytosol (orange) in neurons, including cell body, axon, presynaptic terminals, and most dendrites. (B) Since ER forms a continuous structure that follows the shape of the cell, it has been termed “a neuron within a neuron” (Berridge, 1998, 2002). In the cell body, continuous with the nuclear envelope, is found rough ER, characterized by its sheet-like morphology and the presence of ribosomes (dark blue points) attached to the ER membrane (magnified detail on the left). Peripheral ER (smooth) includes cortical ER in the cell body and dendritic and axonal ER, and is mainly formed by a network of interconnected tubules, with occasional sheets or cisternae (magnified detail on the right). Tubulation of ER membrane is physically promoted by ER-shaping proteins, which share a characteristic intramembrane domain inserted in the cytosolic face of the ER membrane (magnified detail on the bottom right).

FIGURE 2

Tubular ER membrane contact sites (MCSs). Tubular ER membrane forms contacts with other membranes in the cell, including plasma membrane (PM), Golgi, mitochondria, endosomes, lipid droplets (LDs) and peroxisomes. Axonal ER (bottom) also contains MCSs, except with Golgi, due to its absence in axons. ER MCSs can regulate fission of some of the tethered organelles, such as endosomes and mitochondria (dotted circles). ER MCSs (top right) are formed by interactions between ER membrane proteins and proteins found in the other cellular membranes (tethering). This keeps both membranes close enough to allow transfer of lipids and Ca²⁺. Depending on the specific channels localized at each MCS (see main text for details), Ca²⁺ can be released from ER lumen to the other compartment (red) or from other compartment to ER lumen (represented in blue). In both scenarios, Ca²⁺ is released locally to the intramembrane space and then taken up by the acceptor compartment. ER MCSs also mediate non-vesicular and bidirectional transport of lipids, which are shuttled between membranes by lipid transfer proteins (green).

FIGURE 3

Microtubule (MT)-mediated transport of ER tubules. (1) Tip attachment complex (TAC) is formed between a MT plus end and the tip of an ER tubule through STIM1-EB1 interaction, resulting in movement of the ER tubule when the MT grows or retracts. (2) In ER sliding mechanism, the tip of an ER tubule associates to MTs, where motor proteins kinesin and dynein mediates, respectively, anterograde and retrograde movement of the ER tubule.

FIGURE 4

Potential routes underlying axonal ER involvement in neurodegeneration. Bold type shows pathways by which axonal ER may influence other cellular compartments/organelles, where the specific processes regulated in each case are indicated. Blue-border text boxes show processes indirectly regulated by ER. Arrows show regulation of the indicated process. Broken lines show consequences of disrupting the corresponding process.