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

GLP-1 Receptor Agonist NLY01 Reduces Retinal Inflammation and Neuron Death Secondary to Ocular Hypertension

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.

SUMMARY Glaucoma is the leading cause of irreversible blindness worldwide and is characterized by the death of retinal ganglion cells. Reduction of intraocular pressure (IOP) is the only therapeutic mechanism available to slow disease progression. However, glaucoma can continue to progress despite normalization of IOP. New treatments are needed to reduce vision loss and improve outcomes for patients who have exhausted existing therapeutic avenues. Recent studies have implicated neuroinflammation in the pathogenesis of neurodegenerative diseases of both the retina and the brain, including glaucoma and Parkinson’s disease. Pro-inflammatory A1 astrocytes contribute to neuronal cell death in multiple disease processes and have been targeted therapeutically in mouse models of Parkinson’s disease. Microglial release of pro-inflammatory cytokines C1q, IL-1α, and TNF-α is sufficient to drive the formation of A1 astrocytes. The role of A1 astrocytes in glaucoma pathogenesis has not been explored. Using a mouse model of glaucoma, we demonstrated that IOP elevation was sufficient to trigger production of C1q, IL-1α, and TNF-α by infiltrating macrophages followed by resident microglia. These three cytokines drove the formation of A1 astrocytes in the retina. Furthermore, cytokine production and A1 astrocyte transformation persisted following IOP normalization. Ablation of this pathway, by either genetic deletions of C1q, IL-1α, and TNF-α, or treatment with glucagon-like peptide-1 receptor agonist NLY01, reduced A1 astrocyte transformation and RGC death. Together, these results highlight a new neuroinflammatory mechanism behind glaucomatous neurodegeneration that can be therapeutically targeted by NLY01 administration.

/pdf/glp-1r-agonist-nly01-reduces-retinal-inflammation-astrocyte-zw001lmjh6.pdf

GLP-1R agonist NLY01 reduces retinal inflammation, astrocyte reactivity, and retinal ganglion cell death secondary to ocular hypertension

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

Background: Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity / transcriptomic profile of microglia early following ocular hypertensive insults is unknown. 

Methods: To elucidate the molecular identity of microglia during early glaucoma pathogenesis, we performed RNA-sequencing of microglia mRNA from the optic nerve head of a genetic mouse model of glaucoma (DBA/2J) at a time point following ocular hypertensive insults, but preceding detectable neurodegeneration (with microglia identified as being CD45lo/CD11b+/CD11c-). Transcriptomic profiles were compared to other published optic nerve head datasets to assess the contribution of microglia to the signatures discovered in these published data. Furthermore, RNA-sequencing was performed on optic nerve head microglia from mice treated with radiation therapy, a potent therapy preventing neuroinflammatory insults. 

Results: Transcriptomic profiling of optic nerve head microglia mRNA identifies early metabolic priming with marked changes to mitochondria-derived RNA expression, and changes to phagocytosis, inflammatory, and sensome pathways. Comparative analysis of these data with data from previously published whole optic nerve head tissue or monocyte-only samples from DBA/2J mice demonstrate that many of the neuroinflammatory signatures in these data sets arise from infiltrating monocytes and not reactive microglia. Finally, radiation therapy of DBA/2J mice potently abolishes these microglia metabolic transcriptomic changes at the same time points. 

Conclusions: Microglia become metabolically primed early in glaucoma pathogenesis with suppression of homeostatic regulation including phagocytosis, inflammatory, and sensome pathways. These changes are largely prevented by radiation therapy. Neuroinflammatory signatures in DBA/2J glaucoma likely arise from infiltrating monocytes and not from activated or proliferative microglia at this early time point. In addition, our data provide a unique resource for the community to help drive further hypothesis generation and testing.

https://www.biorxiv.org/content/biorxiv/early/2019/11/26/856427.full.pdf

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia

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

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia