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 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.

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

“…Axons are enriched with ER tubules, whilst ER sheets are predominantly found in cell bodies. 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).…”

Axonal Organelles as Molecular Platforms for Axon Growth and Regeneration after Injury

“…In some cases, an individual tubule has been found to span across the entire length of very thin axonal processes while at the same time maintaining its connection with ER in the rest of the cell [ 29 , 30 , 31 ]. This interconnectedness between differently shaped ER structures is essential for axon integrity and function [ 32 ] and is achieved by the function of ER-shaping proteins [ 33 , 34 ]. Mutations in ER-shaping proteins result in human neurological disease, highlighting their importance for proper axonal function [ 35 ].…”

Involvement of Bcl-xL in Neuronal Function and Development

“…In nerve cells, Ca 2+ plays critical roles, notably regarding synaptic transmission [ 39 ]. Given the importance of Ca 2+ -dependent events, a multiplicity of regulatory mechanisms take place to control Ca 2+ homeostasis in neurons, including via the regulation of ER Ca 2+ uptake [ 40 , 41 ].…”