Spinal cord injury disrupts the connections between the brain and spinal cord, often resulting in the loss of sensory and motor function below the lesion site. The most important reason for such permanent functional deficits is the failure of injured axons to regenerate after injury. In principle, the functional recovery could be achieved by two forms of axonal regrowth: the regeneration of lesioned axons which will reconnect with their original targets and the sprouting of spared axons that form new circuits and compensate for the lost function. Our recent studies reveal the activity of the mammalian target of rapamycin (mTOR) pathway, a major regulator of new protein synthesis, as a critical determinant of axon regrowth in the adult retinal ganglion neurons[1]. In this review, I summarize current understanding of the cellular and molecular mechanisms that control the intrinsic regenerative ability of mature neurons.

Intrinsic control of axon regeneration

Our cells are comprised of billions of proteins, lipids, and other small molecules packed into their respective subcellular organelles, with the daunting task of maintaining cellular homeostasis over a lifetime However, it is becoming increasingly evident that organelles do not act as autonomous discrete units but rather as interconnected hubs that engage in extensive communication through membrane contacts In the last few years, our understanding of how these contacts coordinate organelle function has redefined our view of the cell This review aims to present novel findings on the cellular interorganelle communication network and how its dysfunction may contribute to aging and neurodegeneration The consequences of disturbed interorganellar communication are intimately linked with age-related pathologies Given that both aging and neurodegenerative diseases are characterized by the concomitant failure of multiple cellular pathways, coordination of organelle communication and function could represent an emerging regulatory mechanism critical for long-term cellular homeostasis We anticipate that defining the relationships between interorganelle communication, aging, and neurodegeneration will open new avenues for therapeutics

Interorganelle communication, aging, and neurodegeneration

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.

Axonal Endoplasmic Reticulum Dynamics and Its Roles in Neurodegeneration.

Fission of transport tubules from early endosomes is required for endosomal sorting, but mechanisms of endosomal tubule fission (ETF) are incompletely understood. We show protrudin acts at ER-endosome contacts to promote ETF and endosome-to-Golgi traffic. Protrudin-mediated ETF required its ability to interact with ER-localised VAP proteins, endosomal phosphoinositides and KIF5. These properties also regulated the distance between protrudin and endosomal tubules. The defective ETF phenotype of increased endosomal tubulation in cells lacking protrudin was phenocopied by depletion of KIF5, but not FYCO1, a motor protein adaptor implicated in protrudin-dependent late endosome motility. It also required intact microtubules and dynein, consistent with a model where protrudin facilitates a tug-of-war between KIF5 and dynein to fission tubules. In addition to its direct role, protrudin links many other machineries involved in ETF, thus our findings elucidate how ETF is co-ordinated. These machineries are enriched for proteins implicated in hereditary motor neuron disorders, and protrudin or KIF5 depletion caused defective ETF in human neurons. 

Protrudin acts at ER-endosome contacts to promote KIF5-mediated endosomal fission and endosome-to-Golgi transport

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 Protrudin9s 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 important roles for these cellular components in mediating regeneration in the adult central nervous system.

https://www.biorxiv.org/content/biorxiv/early/2020/03/23/2020.01.15.907550.full.pdf

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

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