Decreased Energy Capacity and Increased Autophagic Activity in Optic Nerve Axons With Defective Anterograde Transport

Kleesattel, David; Crish, Samuel D.; Inman, Denise M.

doi:10.1167/iovs.15-17885

Cited by 39 publications

(27 citation statements)

References 40 publications

(58 reference statements)

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“…We observed a linear relationship between mitochondrial volume and axon volume in DBA/2J-Gpnmb + (control strain that does not develop glaucoma) and pre-pathological D2 optic nerve. That relationship is abolished in the transport dysfunctional D2 optic nerve, for which we observed axon volumes that were not matched by appropriate mitochondrial volumes (Kleesattel et al, 2015). Interestingly, CAP amplitude measures suggest that the third peak of the CAP trace, corresponding to the slowest conducting axons, are lost earliest and in the greatest numbers, and in accordance to magnitude of IOP exposure, in the D2 mouse model of glaucoma (see Figure 1; Baltan et al, 2010).…”

Section: Energy and Glaucoma-specific Axon Degenerationmentioning

confidence: 72%

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Inman

Harun‐Or‐Rashid

2017

Front. Neurosci.

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Axons can be several orders of magnitude longer than neural somas, presenting logistical difficulties in cargo trafficking and structural maintenance. Keeping the axon compartment well supplied with energy also presents a considerable challenge; even seemingly subtle modifications of metabolism can result in functional deficits and degeneration. Axons require a great deal of energy, up to 70% of all energy used by a neuron, just to maintain the resting membrane potential. Axonal energy, in the form of ATP, is generated primarily through oxidative phosphorylation in the mitochondria. In addition, glial cells contribute metabolic intermediates to axons at moments of high activity or according to need. Recent evidence suggests energy disruption is an early contributor to pathology in a wide variety of neurodegenerative disorders characterized by axonopathy. However, the degree to which the energy disruption is intrinsic to the axon vs. associated glia is not clear. This paper will review the role of energy availability and utilization in axon degeneration in glaucoma, a chronic axonopathy of the retinal projection.

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Section: Energy and Glaucoma-specific Axon Degenerationmentioning

confidence: 72%

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Inman

Harun‐Or‐Rashid

2017

Front. Neurosci.

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“…Activated NFκB can enhance mitochondrial bioenergetics and prevent peripheral neuropathy in rodent models of diabetes (Saleh et al, 2013 ). Increased NFκB localization to RGC nuclei in HE3286-treated microbead-injected eyes may protect these neurons metabolically (Kong et al, 2009 ; Baltan et al, 2010 ; Lee et al, 2011 ; Coughlin et al, 2015 ; Kleesattel et al, 2015 ; Fahy et al, 2016 ), such that axonal transport is preserved compared to vehicle-treated eyes (Figure 2 ). Whether or not HE3286 maintains RGC functionality could be assessed using outcomes such as visual evoked potentials, electroretinogram, or two-alternative forced-choice visual behavioral testing in this or other models of glaucoma.…”

Section: Discussionmentioning

confidence: 99%

Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma

et al. 2017

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Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease is the leading cause of irreversible blindness worldwide. Early progression in glaucoma involves dysfunction of retinal ganglion cell (RGC) axons, which comprise the optic nerve. Deficits in anterograde transport along RGC axons to central visual structures precede outright degeneration, and preventing these deficits is efficacious at abating subsequent progression. HE3286 is a synthetic sterol derivative that has shown therapeutic promise in models of inflammatory disease and neurodegenerative disease. We examined the efficacy of HE3286 oral delivery in preventing loss of anterograde transport in an inducible model of glaucoma (microbead occlusion). Adult rats received HE3286 (20 or 100 mg/kg) or vehicle daily via oral gavage for 4 weeks. Microbead occlusion elevated IOP ~30% in all treatment groups, and elevation was not affected by HE3286 treatment. In the vehicle group, elevated IOP reduced anterograde axonal transport to the superior colliculus, the most distal site in the optic projection, by 43% (p = 0.003); HE3286 (100 mg/kg) prevented this reduction (p = 0.025). HE3286 increased brain-derived neurotrophic factor (BDNF) in the optic nerve head and retina, while decreasing inflammatory and pathogenic proteins associated with elevated IOP compared to vehicle treatment. Treatment with HE3286 also increased nuclear localization of the transcription factor NFκB in collicular and retinal neurons, but decreased NFκB in glial nuclei in the optic nerve head. Thus, HE3286 may have a neuroprotective influence in glaucoma, as well as other chronic neurodegenerations.

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“…Autophagy describes the orderly self-degradation and recycling of unwanted or dysfunctional cellular components and is used by terminally differentiated cells to manage their cytoskeletal and organelle turnover [101]. Autophagy can be upregulated in response to cellular stress [102] and dysregulation of this process is increasingly associated with neuropathological conditions, including Alzheimer’s and Parkinson’s diseases [134].…”

Section: Mechanisms Of Rgc and Axonal Deathmentioning

confidence: 99%

“…Autophagy can be upregulated in response to cellular stress [102] and dysregulation of this process is increasingly associated with neuropathological conditions, including Alzheimer’s and Parkinson’s diseases [134]. In glaucoma models, an apparent upregulation of autophagy (via increased observance of autophagosomes) is reported in RGC soma [38], and dysregulation of autophagic flux is reported in RGC axons in response to downregulation of anterograde axonal transport in the murine DBA/2 J glaucoma model [101]. …”

Section: Mechanisms Of Rgc and Axonal Deathmentioning

confidence: 99%

Glaucoma: the retina and beyond

Davis¹,

Crawley

Pahlitzsch³

et al. 2016

Acta Neuropathol

228

151

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Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of recent developments in techniques for monitoring RGC health is provided, including recent progress towards the development of RGC specific contrast agents. The review concludes by discussing techniques to assess glaucomatous changes in the brain using MRI and the clinical relevance of glaucomatous-associated changes in the visual centres of the brain.

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Decreased Energy Capacity and Increased Autophagic Activity in Optic Nerve Axons With Defective Anterograde Transport

Cited by 39 publications

References 40 publications

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Metabolic Vulnerability in the Neurodegenerative Disease Glaucoma

Oral Delivery of a Synthetic Sterol Reduces Axonopathy and Inflammation in a Rodent Model of Glaucoma

Glaucoma: the retina and beyond

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