Proximal inhibition of p38 MAPK stress signaling prevents distal axonopathy
Glaucoma; Neurodegeneration; Neurosciences & Neurology; death; amyotrophic-lateral-sclerosis; mouse model; ocular hypertension; activated protein-kinase; up-regulation; alzheimers-disease brain; Axonopathy; experimental glaucoma; ganglion-cell neurons; Heat shock protein; p38 MAPK; rat retina; Retinal ganglion cell
The p38 mitogen-activated protein kinase (MAPK) isoforms are phosphorylated by a variety of stress stimuli in neurodegenerative disease and act as upstream activators of myriad pathogenic processes. Thus, p38 MAPK inhibitors are of growing interest as possible therapeutic interventions. Axonal dysfunction is an early component of most neurodegenerative disorders, including the most prevalent optic neuropathy, glaucoma. Sensitivity to intraocular pressure at an early stage disrupts anterograde transport along retinal ganglion cell (RGC) axons to projection targets in the brain with subsequent degeneration of the axons themselves; RGC body loss is much later. Here we show that elevated ocular pressure in rats increases p38 MAPK activation in retina, especially in RGC bodies. Topical eye-drop application of a potent and selective inhibitor of the p38 MAPK catalytic domain (Ro3206145) prevented both the degradation of anterograde transport to the brain and degeneration of axons in the optic nerve. Ro3206145 reduced in the retina phosphorylation of tau and heat-shock protein 27, both down-stream targets of p38 IVIAPK activation implicated in glaucoma, as well as expression of two inflammatory responses. We also observed increased p38 MAPK activation in mouse models. Thus, inhibition of p38 MAPK signaling in the retina may represent a therapeutic target for preventing early pathogenesis in optic neuropathies. (C) 2013 Elsevier Inc. All rights reserved.
Dapper J D; Crish S D; Pang I H; Calkins D J
Neurobiology of Disease
2013
2013-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/j.nbd.2013.07.001" target="_blank" rel="noreferrer noopener">10.1016/j.nbd.2013.07.001</a>
Failure of axonal transport induces a spatially coincident increase in astrocyte BDNF prior to synapse loss in a central target.
Animal; Animals; Astrocytes/*metabolism; Axonal Transport/*physiology; Brain-Derived Neurotrophic Factor/*metabolism; Disease Models; Glaucoma/genetics/*metabolism; Messenger/genetics/metabolism; Mice; Optic Nerve Diseases/genetics/metabolism; Rats; Retinal Ganglion Cells/*metabolism; RNA; Superior Colliculi/metabolism; Synapses/*metabolism; Visual Pathways/metabolism
Failure of anterograde transport to distal targets in the brain is a common feature of neurodegenerative diseases. We have demonstrated in rodent models of glaucoma, the most common optic neuropathy, early loss of anterograde transport along the retinal ganglion cell (RGC) projection to the superior colliculus (SC) is retinotopic and followed by a period of persistence of RGC axon terminals and synapses through unknown molecular pathways. Here we use the DBA/2J mouse model of hereditary glaucoma and an acute rat model to demonstrate that retinotopically focal transport deficits in the SC are accompanied by a spatially coincident increase in brain-derived neurotrophic factor (BDNF), especially in hypertrophic astrocytes. These neurochemical changes occur prior to loss of RGC synapses in the DBA/2J SC. In contrast to BDNF protein, levels of Bdnf mRNA decreased with transport failure, even as mRNA encoding synaptic structures remained unchanged. In situ hybridization signal for Bdnf mRNA was the strongest in SC neurons, and labeling for the immature precursor pro-BDNF was very limited. Subcellular fractionation of SC indicated that membrane-bound BDNF decreased with age in the DBA/2J, while BDNF released from vesicles remained high. These results suggest that in response to diminished axonal function, activated astrocytes in the brain may sequester mature BDNF released from target neurons to counter stressors that otherwise would challenge survival of projection synapses.
Crish S D; Dapper J D; MacNamee S E; Balaram P; Sidorova T N; Lambert W S; Calkins D J
Neuroscience
2013
2013-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.neuroscience.2012.10.069" target="_blank" rel="noreferrer noopener">10.1016/j.neuroscience.2012.10.069</a>