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Glial cells and neurons are engaged in a continuous and highly regulated bidirectional dialog. A remarkable example is the control of myelination. Oligodendrocytes in the central nervous system (CNS) and Schwann cells (SCs) in the peripheral nervous system (PNS) wrap their plasma membranes around axons to organize myelinated nerve fibers that allow rapid saltatory conduction. The functionality of this system is critical, as revealed by numerous neurological diseases that result from deregulation of the system, including multiple sclerosis and peripheral neuropathies. In this review we focus on PNS myelination and present a conceptual framework that integrates crucial signaling mechanisms with basic SC biology. We will highlight signaling hubs and overarching molecular mechanisms, including genetic, epigenetic, and post-translational controls, which together regulate the interplay between SCs and axons, extracellular signals, and the transcriptional network.

Glaucoma is defined as a chronic and progressive optic nerve neuropathy, characterized by apoptosis of retinal ganglion cells (RGC) that leads to irreversible blindness. Ocular hypertension is a major risk factor, but in glaucoma RGC death can persist after ocular hypertension is normalized. To understand the mechanism underlying chronic RGC death we identified and characterized a gene product, alpha2-macroglobulin (alpha2M), whose expression is up-regulated early in ocular hypertension and remains up-regulated long after ocular hypertension is normalized. In ocular hypertension retinal glia up-regulate alpha2M, which binds to low-density lipoprotein receptor-related protein-1 receptors in RGCs, and is neurotoxic in a paracrine fashion. Neutralization of alpha2M delayed RGC loss during ocular hypertension; whereas delivery of alpha2M to normal eyes caused progressive apoptosis of RGC mimicking glaucoma without ocular hypertension. This work adds to our understanding of the pathology and molecular mechanisms of glaucoma, and illustrates emerging paradigms for studying chronic neurodegeneration in glaucoma and perhaps other disorders.

Molecular neurobiology, 44 (3), ISSN:0893-7648, ISSN:1559-1182

Glaucoma is an optic neuropathy characterized by progressive death of retinal ganglion cells (RGCs) and optic nerve degeneration leading to irreversible vision loss. Elevated intraocular pressure is a major risk factor in glaucoma. Open angle and angleclosure glaucoma, the most common forms of the disease, are often associated with high intraocular pressure (IOP). The current standard therapy for glaucoma is to lower eye pressure by medication (e.g., prostaglandin therapy) or surgery. However, there are risks and adverse side effects associated with these treatments (1). More importantly, a significant number of patients continue to experience visual loss despite responding well to pressure-lowering medications (2–5). Therefore, current therapeutic strategies for glaucoma are insufficient, and new approaches to slow disease progression are urgently needed. The primary mechanism of RGC damage in glaucoma is not well understood, but there is convincing evidence that neuronal loss in this disease occurs by apoptosis (6,7). This self-destructive, genetically driven death program is activated in all neurons. It is now widely accepted that neurotrophic factors promote neuronal survival by inhibiting default apoptotic pathways (8). For example, there is strong direct evidence

A hallmark of glaucomatous optic nerve damage is retinal ganglion cell (RGC) death. RGCs, like other central nervous system neurons, have a limited capacity to survive or regenerate an axon after injury. Strategies that prevent or slow down RGC degeneration, in combination with intraocular pressure management, may be beneficial to preserve vision in glaucoma. Recent progress in neurobiological research has led to a better understanding of the molecular pathways that regulate the survival of injured RGCs. Here we discuss a variety of experimental strategies including intraocular delivery of neuroprotective molecules, viral-mediated gene transfer, cell implants and stem cell therapies, which share the ultimate goal of promoting RGC survival after optic nerve damage. The challenge now is to assess how this wealth of knowledge can be translated into viable therapies for the treatment of glaucoma and other optic neuropathies.

Little is known about the molecular mechanisms that limit the ability of retinal neurons to respond to neurotrophic factor stimulation following axonal injury. In the adult retina, nerve growth factor (NGF) binds to TrkA (expressed by neurons) and p75(NTR) (expressed by Muller glia), but fails to promote the survival of axotomized retinal ganglion cells (RGCs). We addressed the functional role of TrkA and p75(NTR) in this lack of survival by using peptidomimetic agonistic or antagonistic ligands specific for each receptor. While administration of exogenous NGF failed to rescue axotomized RGCs, administration of selective TrkA agonists led to robust neuroprotection. Surprisingly, we found a remarkable survival of axotomized RGCs following pharmacological inhibition of p75(NTR) or in p75(NTR) knockout mice. Combination of NGF or TrkA agonists with p75(NTR) antagonists further potentiated RGC neuroprotection in vivo, an effect that was greater than each treatment alone. NGF can therefore be neuroprotective when acting on neuronal TrkA receptors but engagement of p75(NTR) on glial cells antagonizes this effect. Our data reveal a novel mechanism by which p75(NTR) expressed on retinal glia can profoundly influence neuronal survival.

Histones deacetylases (HDACs), besides their function as epigenetic regulators, deacetylate and critically regulate the activity of nonhistone targets. In particular, HDACs control partially the proapoptotic activity of p53 by balancing its acetylation state. HDAC inhibitors have revealed neuroprotective properties in different models, but the exact mechanisms of action remain poorly understood. We have generated a conditional knockout mouse model targeting retinal ganglion cells (RGCs) to investigate specifically the functional role of HDAC1 and HDAC2 in an acute model of optic nerve injury. Our results demonstrate that combined HDAC1 and HDAC2 ablation promotes survival of axotomized RGCs. Based on global gene expression analyses, we identified the p53-PUMA apoptosis-inducing axis to be strongly activated in axotomized mouse RGCs. Specific HDAC1/2 ablation inhibited this apoptotic pathway by impairing the crucial acetylation status of p53 and reducing PUMA expression, thereby contributing to the ensuing enhanced neuroprotection due to HDAC1/2 depletion. HDAC1/2 inhibition and the affected downstream signaling components emerge as specific targets for developing therapeutic strategies in neuroprotection., ASN Neuro, 7 (3), ISSN:1759-0914