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Adaptive responses to neurodegenerative stress in glaucoma.
Prog Retin Eye Res. 2021 Sep; 84:100953.PR

Abstract

Glaucoma causes loss of vision through degeneration of the retinal ganglion cell (RGC) projection to the brain. The disease is characterized by sensitivity to intraocular pressure (IOP) conveyed at the optic nerve head, through which RGC axons pass unmyelinated to form the optic nerve. From this point, a pathogenic triumvirate comprising inflammatory, oxidative, and metabolic stress influence both proximal structures in the retina and distal structures in the optic projection. This review focuses on metabolic stress and how the optic projection may compensate through novel adaptive mechanisms to protect excitatory signaling to the brain. In the retina and proximal nerve head, the unmyelinated RGC axon segment is energy-inefficient, which leads to increased demand for adenosine-5'-triphosphate (ATP) at the risk of vulnerability to Ca2+-related metabolic and oxidative pressure. This vulnerability may underlie the bidirectional nature of progression. However, recent evidence highlights that the optic projection in glaucoma is not passive but rather demonstrates adaptive processes that may push back against neurodegeneration. In the retina, even as synaptic and dendritic pruning ensues, early progression involves enhanced excitability of RGCs. Enhancement involves depolarization of the resting membrane potential and increased response to light, independent of RGC morphological type. This response is axogenic, arising from increased levels and translocation of voltage-gated sodium channels (NaV) in the unmyelinated segment. During this same early period, large-scale networks of gap-junction coupled astrocytes redistribute metabolic resources to the optic projection stressed by elevated IOP to slow loss of axon function. This redistribution may reflect more local remodeling, as astrocyte processes respond to focal metabolic duress by boosting glycogen turnover in response to axonal activity in an effort to promote survival of the healthiest axons. Both enhanced excitability and metabolic redistribution are transient, indicating that the same adaptive mechanisms that apparently serve to slow progression ultimately may be too expensive for the system to sustain over longer periods.

Authors+Show Affiliations

The Vanderbilt Eye Institute, Nashville, TN, USA; Vanderbilt Vision Research Center, Vanderbilt University Medical Center, 1161 21st Ave S, AA7100 Medical Center North Nashville, Tennessee, 37232, USA. Electronic address: david.j.calkins@vumc.org.

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

33640464

Citation

Calkins, David J.. "Adaptive Responses to Neurodegenerative Stress in Glaucoma." Progress in Retinal and Eye Research, vol. 84, 2021, p. 100953.
Calkins DJ. Adaptive responses to neurodegenerative stress in glaucoma. Prog Retin Eye Res. 2021;84:100953.
Calkins, D. J. (2021). Adaptive responses to neurodegenerative stress in glaucoma. Progress in Retinal and Eye Research, 84, 100953. https://doi.org/10.1016/j.preteyeres.2021.100953
Calkins DJ. Adaptive Responses to Neurodegenerative Stress in Glaucoma. Prog Retin Eye Res. 2021;84:100953. PubMed PMID: 33640464.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adaptive responses to neurodegenerative stress in glaucoma. A1 - Calkins,David J, Y1 - 2021/02/25/ PY - 2020/11/09/received PY - 2021/02/08/revised PY - 2021/02/19/accepted PY - 2022/09/01/pmc-release PY - 2021/3/1/pubmed PY - 2021/3/1/medline PY - 2021/2/28/entrez KW - Adaptive remodeling KW - Astrocytes KW - Axon degeneration KW - Gap junctions KW - Glaucoma KW - Metabolic stress KW - Neurodegeneration KW - Oxidative stress SP - 100953 EP - 100953 JF - Progress in retinal and eye research JO - Prog Retin Eye Res VL - 84 N2 - Glaucoma causes loss of vision through degeneration of the retinal ganglion cell (RGC) projection to the brain. The disease is characterized by sensitivity to intraocular pressure (IOP) conveyed at the optic nerve head, through which RGC axons pass unmyelinated to form the optic nerve. From this point, a pathogenic triumvirate comprising inflammatory, oxidative, and metabolic stress influence both proximal structures in the retina and distal structures in the optic projection. This review focuses on metabolic stress and how the optic projection may compensate through novel adaptive mechanisms to protect excitatory signaling to the brain. In the retina and proximal nerve head, the unmyelinated RGC axon segment is energy-inefficient, which leads to increased demand for adenosine-5'-triphosphate (ATP) at the risk of vulnerability to Ca2+-related metabolic and oxidative pressure. This vulnerability may underlie the bidirectional nature of progression. However, recent evidence highlights that the optic projection in glaucoma is not passive but rather demonstrates adaptive processes that may push back against neurodegeneration. In the retina, even as synaptic and dendritic pruning ensues, early progression involves enhanced excitability of RGCs. Enhancement involves depolarization of the resting membrane potential and increased response to light, independent of RGC morphological type. This response is axogenic, arising from increased levels and translocation of voltage-gated sodium channels (NaV) in the unmyelinated segment. During this same early period, large-scale networks of gap-junction coupled astrocytes redistribute metabolic resources to the optic projection stressed by elevated IOP to slow loss of axon function. This redistribution may reflect more local remodeling, as astrocyte processes respond to focal metabolic duress by boosting glycogen turnover in response to axonal activity in an effort to promote survival of the healthiest axons. Both enhanced excitability and metabolic redistribution are transient, indicating that the same adaptive mechanisms that apparently serve to slow progression ultimately may be too expensive for the system to sustain over longer periods. SN - 1873-1635 UR - https://www.unboundmedicine.com/medline/citation/33640464/Adaptive_responses_to_neurodegenerative_stress_in_glaucoma. L2 - https://scite.ai/reports/33640464 DB - PRIME DP - Unbound Medicine ER -
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