Traumatology of the optic nerve and contribution of crystallins to axonal regeneration

Abstract

Within a few decades, the repair of long neuronal pathways such as spinal cord tracts, the optic nerve or intracerebral tracts has gone from being strongly contested to being recognized as a potential clinical challenge. Cut axonal stumps within the optic nerve were originally thought to retract and become irreversibly necrotic within the injury zone. Optic nerve astrocytes were assumed to form a gliotic scar and remodelling of the extracellular matrix to result in a forbidden environment for re-growth of axons. Retrograde signals to the ganglion cell bodies were considered to prevent anabolism, thus also initiating apoptotic death and gliotic repair within the retina. However, increasing evidence suggests the reversibility of these regressive processes, as shown by the analysis of molecular events at the site of injury and within ganglion cells. We review optic nerve repair from the perspective of the proximal axon stump being a major player in determining the successful formation of a growth cone. The axonal stump and consequently the prospective growth cone, communicates with astrocytes, microglial cells and the extracellular matrix via a panoply of molecular tools. We initially highlight these aspects on the basis of recent data from numerous laboratories. Then, we examine the mechanisms by which an injury-induced growth cone can sense its surroundings within the area distal to the injury. Based on requirements for successful axonal elongation within the optic nerve, we explore the models employed to instigate successful growth cone formation by ganglion cell stimulation and optic nerve remodelling, which in turn accelerate growth. Ultimately, with regard to the proteomics of regenerating retinal tissue, we discuss the discovery of isoforms of crystallins, with crystallin beta-b2 (crybb2) being clearly upregulated in the regenerating retina. Crystallins are produced and used to promote the elongation of growth cones. In vivo and in vitro, crystallins beta and gamma additionally promote the growth of axons by enhancing the production of ciliary neurotrophic factor (CNTF), indicating that they also act on astrocytes to promote axonal regrowth synergistically. These are the first data showing that axonal regeneration is related to crybb2 movement within neurons and to additional stimulation of CNTF. We demonstrate that neuronal crystallins constitute a novel class of neurite-promoting factors that probably operate through an autocrine and paracrine mechanism and that they can be used in neurodegenerative diseases. Thus, the post-injury fate of neurons cannot be seen merely as inevitable but, instead, must be regarded as a challenge to shape conditions for initiating growth cone formation to repair the damaged optic nerve.

Discovery of new glomerular disease–relevant genes by translational profiling of podocytes in vivo

“…Other notable, strongly induced genes in Actn4 −/− podocytes included crystalline, gamma N (Crygn), a member of the crystallin superfamily that shows neurite-promoting properties through putative autocrine and paracrine effects (37, 38), the regulatory protein ‘growth arrest and DNA-damage-inducible 45 beta’ (Gadd45b), which has only recently been demonstrated to promote adult neurogenesis via epigenetic DNA demethylation (39), and toll-like receptor 4 (Tlr4), which has been suggested to directly associate the podocyte with the innate immune system to mediate glomerular injury in membranoproliferative glomerulonephritis (40) and which may offer a mechanistic link to the observed upregulation of Cxcl1 and other NF-κB-regulated genes. Among genes that were ≥2-fold downregulated in Actn4 −/− podocytes we identified e.g.…”

βA3/A1-crystallin: More than a lens protein

“…They also showed that addition of exogenous β/γ-crystallins (1 mg injected intravitreally in the rat eye) activated retinal glial cells, stimulating astrocytes to secrete ciliary neurotrophic factor (CNTF) and up-regulating its downstream signaling pathway (JAK/STAT3). These studies, which have been recently reviewed by Thanos et al, (2012), suggest that β/γ-crystallins are able to alter the activity of signaling pathways by a mechanism, or mechanisms, yet to be identified.…”

BetaB2-crystallin mutations associated with cataract and glaucoma leads to mitochondrial alterations in lens epithelial cells and retinal neurons

“…Indeed, crystallin mutations associated with cataract often lead to protein aggregation; however, little data has been reported for βB2-crystallin aggregation (Chen et al, 2013; Liu and Liang, 2005; Moreau and King, 2012a, b; Raju and Abraham, 2011). In addition, βB2-crystallin is also expressed in the retina and plays a key role in the protection of retinal neurons and the regeneration of their processes, critical aspects of the pathophysiology of glaucoma (Bohm et al, 2015; Prokosch et al, 2013; Thanos et al, 2012). …”