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Editors Selection IGR 17-4
Basic Research: ASK-1 deficiency in an NTG model
Comment by Makoto Aihara on:
25929 ASK1 deficiency attenuates neural cell death in GLAST-deficient mice, a model of normal tension glaucoma, Harada C; Namekata K; Guo X et al., Cell Death and Differentiation, ;
NTG is a kind of multi-factorial chronic disorder of optic nerve axons, quite resembling IOP-dependent optic nerve degenerations. Harada et al. (648) already published GLAST-deficient mice as a NTG model, in which RGC apoptosis is induced by excessive extracellular glutamate and/or oxidative stress due to decreased uptake of glutamate into glial cells by a glutamate transporter, GLAST. Next, they established GLAST and ASK-1 double transgenic mice, to investigate the effect of ASK-1 (MAPKKK) on RGC apoptosis. As a result, ASK-1 rescued RGC death of GLAST-deficient mice. Thus, ASK-1 may be a key role to prevent glutamate- or oxidative stress-induced RGC death. However, in the original GLAST-deficient mice, the RGCs degenerated quickly in the initial eight weeks and become stable later. Thus, this NTG model is a subacute RGC degenerative model, and not a chronic model for a chronic disease like NTG. Of course, glutamate and oxidative stress are well-known risk factors inducing RGC apoptosis in experimental glaucoma studies as well as IOP elevation or ischemia. To this point, ASK-1 may be a candidate neuroprotective agent in NTG or other neurodegenerative disorders. In general, this model or other NTG models still face a dilemma in clinical relevance between the experimental result and clinical NTG. These animal glaucoma models with normal IOP established by modifying a known target molecule should be considered optic nerve degeneration models with normal IOP, and are not equivalent to human NTG. Nobody knows how factors such as GLAST dysfunction, disturbed glutamate balance, oxidative stress, or ASK-1 contribute to the pathogenesis of glaucoma. Already we have many risk factors and protective agents against these factors in glaucoma as well as IOP and IOP-lowering drugs. As a next step we should verify the beneficial effect of the target protective molecules on NTG patients, or dig out the target molecules which have been already verified in the animal NTG models. Unfortunately, the past neuroprotective clinical trials have not been successful, and finding a target molecule from NTG patients with various background and risk factors is quite difficult. However, proceeding step by step is required for any future glaucoma therapy that protect RGCs or reduces IOP.
In general, this model or other NTG models still face a dilemma in clinical relevance between the experimental result and clinical NTG.
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