In Vivo Imaging of Secondary Neurodegeneration Associated With Phosphatidylserine Externalization Along Axotomized Axons.

Purpose: Axonal degeneration in acute and chronic disorders is well-characterized, comprising retrograde (proximal) and Wallerian (distal) degeneration, but the mechanism of propagation remains less understood.

Methods: Laser injury with a diode-pumped solid-state 532 nm laser was used to axotomize retinal ganglion cell axons. We used confocal in vivo imaging to demonstrate that phosphatidylserine externalization is a biomarker of early axonal degeneration after selective intraretinal axotomy.

Pivotal roles for membrane phospholipids in axonal degeneration.

Membrane phospholipids are critical components of several signaling pathways. Maintained in a variety of asymmetric distributions, their trafficking across the membrane can be induced by intra-, extra-, and intercellular events. A familiar example is the externalization of phosphatidylserine from the inner leaflet to the outer leaflet in apoptosis, inducing phagocytosis of the soma.

Axonal degeneration induces distinct patterns of phosphatidylserine and phosphatidylethanolamine externalization.

Axonal degeneration is a common feature of multiple neurodegenerative diseases, yet the mechanisms underlying its various manifestations are incompletely understood. We previously demonstrated that axonal degeneration is associated with externalization of phosphatidylserine (PS), which precedes morphological evidence of degeneration, is redox-sensitive, and is delayed in Wallerian degeneration slow (Wld) mutant animals. Phosphatidylethanolamine (PE) is the other major membrane phospholipid in the inner leaflet of the cell membrane, and given that PS signals apoptosis, phagocytosis, and degeneration, we hypothesized that PS and PE membrane dynamics play distinct roles in axonal degeneration.

Cobalamin-Associated Superoxide Scavenging in Neuronal Cells Is a Potential Mechanism for Vitamin B-Deprivation Optic Neuropathy.

Chronic deficiency of vitamin B is the only nutritional deficiency definitively proved to cause optic neuropathy and loss of vision. The mechanism by which this occurs is unknown. Optic neuropathies are associated with death of retinal ganglion cells (RGCs), neurons that project their axons along the optic nerve to the brain.

Neuroprotection in Glaucoma: Animal Models and Clinical Trials.

Glaucoma is a progressive neurodegenerative disease that frequently results in irreversible blindness. Glaucoma causes death of retinal ganglion cells (RGCs) and their axons in the optic nerve, resulting in visual field deficits and eventual loss of visual acuity. Glaucoma is a complex optic neuropathy, and a successful strategy for its treatment requires not only better management of known risk factors such as elevated intraocular pressure and the development of improved tools for detecting RGC injury but also treatments that address this injury (i.

Axonal Degeneration in Retinal Ganglion Cells Is Associated with a Membrane Polarity-Sensitive Redox Process.

Axonal degeneration is a pathophysiological mechanism common to several neurodegenerative diseases. The slow Wallerian degeneration (Wld) mutation, which results in reduced axonal degeneration in the central and peripheral nervous systems, has provided insight into a redox-dependent mechanism by which axons undergo self-destruction. We studied early molecular events in axonal degeneration with single-axon laser axotomy and time-lapse imaging, monitoring the initial changes in transected axons of purified retinal ganglion cells (RGCs) from wild-type and Wld rat retinas using a polarity-sensitive annexin-based biosensor (annexin B12-Cys101,Cys260-N,N'-dimethyl-N-(iodoacetyl)-N'-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) ethylenediamine).

Ultrastructural maturation of human bone marrow mesenchymal stem cells-derived cardiomyocytes under alternative induction of 5-azacytidine.

Adult cardiomyocytes lack the ability to proliferate and are unable to repair damaged heart tissue, therefore differentiation of stem cells to cardiomyocytes represents an exceptional opportunity to study cardiomyocytes in vitro and potentially provides a valuable source for replacing damaged tissue. However, characteristic maturity of the in vitro differentiated cardiomyocytes and methods to achieve it are yet to be optimized. In this study, differentiation of human bone marrow-mesenchymal stem cells (hBM-MSCs) into cardiomyocytes is accomplished and the process investigated ultrastructurally.

Acetylcholinesterase inhibition promotes retinal vasoprotection and increases ocular blood flow in experimental glaucoma.

Purpose: A clear correlation between vascular deficits and retinal ganglion cell (RGC) loss in glaucoma has not yet been established. The question arose as to whether there is loss of inner retinal vessels following intraocular pressure (IOP) increase and, if so, whether it occurs prior to, concomitantly with, or after RGC death. We also sought to establish whether galantamine, an acetylcholinesterase inhibitor that promotes RGC survival, can protect the retinal microvasculature and enhance blood flow in experimental glaucoma.

The molecular basis of retinal ganglion cell death in glaucoma.

Glaucoma is a group of diseases characterized by progressive optic nerve degeneration that results in visual field loss and irreversible blindness. A crucial element in the pathophysiology of all forms of glaucoma is the death of retinal ganglion cells (RGCs), a population of CNS neurons with their soma in the inner retina and axons in the optic nerve. Strategies that delay or halt RGC loss have been recognized as potentially beneficial to preserve vision in glaucoma; however, the success of these approaches depends on an in-depth understanding of the mechanisms that lead to RGC dysfunction and death.

A cell-permeable phosphine-borane complex delays retinal ganglion cell death after axonal injury through activation of the pro-survival extracellular signal-regulated kinases 1/2 pathway.

The reactive oxygen species (ROS) superoxide has been recognized as a critical signal triggering retinal ganglion cell (RGC) death after axonal injury. Although the downstream targets of superoxide are unknown, chemical reduction of oxidized sulfhydryls has been shown to be neuroprotective for injured RGCs. On the basis of this, we developed novel phosphine-borane complex compounds that are cell permeable and highly stable.

Maintenance of axo-oligodendroglial paranodal junctions requires DCC and netrin-1.

Paranodal axoglial junctions are essential for the segregation of myelinated axons into distinct domains and efficient conduction of action potentials. Here, we show that netrin-1 and deleted in colorectal cancer (DCC) are enriched at the paranode in CNS myelin. We then address whether netrin-1 signaling influences paranodal adhesion between oligodendrocytes and axons.