Can cerebrospinal fluid pressure influence optic nerve head neuropathy in glaucoma?2

Optom
In my last blog on this topic, I presented cerebrospinal fluid pressure as a factor of Normal Tension Glaucoma. This could explain the reason behind the seemingly 'low' to 'normal' IOP is this group of Open angle glaucoma types. But does it totally explain the optic nerve head neuropathy?
Optic nerve head neuropathy is a function of optic nerve fibre deaths otherwise known as optic nerve fibre apoptosis. What is responsible for optic nerve fibre apoptosis in NTG? It is true that the translaminar pressure gradient on the lamina cribosa skews it posteriorly, distorting it & oftentimes disrupting its normal physiological function. It could be theorized that @ this point the optic nerve fibres start degenerating, dying off & replaced by the neuropathy @ the disk head! Two types of gene mutations is said to be associated with glaucomatous optic nerve head neuropathy- Optoneurin mutation on gene OPTN & Myocilin/trabecular meshwork glucocorticoid inducible response mutation.
Optoneurin is a coiled protein that was first identified for its anti-apoptotic activity against a genetic strain of adenovirus protein (E3-14.7K). Tumour necrosis factor alpha (TNF-alpha) stimulates the activities of Optoneurin. Optoneurin protein plays a neuro-protective role in the eyes where it is found in the retina, the non-pigmentent cilliary epithelium, the optic nerve head, the lamina cribosa and in the trabecular meshwork. It is also known for its ability to interact with tranferrin via the transferrin receptors which influences the axiomatic flow of optic nerve fibres. Over-espression of optoneurin can induce the formation of a mutant type of optoneurin that has been shown to cause retinal ganglion cell apoptosis, the E50K.
E50K mutant is a variant of Optoneurin protein that is known to stimulate cell apoptosis using Tumour Necrosis Factor alpha (TNF-alpha) as a catalyst, just like in the normal optoneurin response. Hence instead of performing its intended anti-apoptotic function, E50K has been found to stimulate retinal ganglion cell degeneration in the retina & in the optic nerve head consistant with glaucomatous optic nerve neuropathy. Again, the secretion of TNF-alpha in the retinal area is achieved over-time by stimulated ischaemia of the optic nerve vessels & elevated hydrostatic (a.k.a. translaminar) pressure in return this causes the cellular 'insult' that will produce more mutant Optoneurin in a viscious cycle of retinal ganglion cell deaths beginning from the periphery to the optic nerve head. Also the mutant E50K often interferes with the 'normal' interaction of the Optoneurin with tranferrin which influences axiomatic flow in the optic nerve fibres. E50K "dumps" the tranferrin which consequently alters axiomatic flow & hence apoptosis of nerve cell fibres if the altered axiomatic flow is not 'repaired'. About 17% cases of Normal Tension Glaucoma (NTG) patients are reported to show increased presence of mutant Optoneurin, E50K.
Myocilin, Trabecular meshwork inducible glucocorticiod response (TIGR), is a protein which in human is encoded by the MYOC gene. The MYOC gene is known to have a signal sequence, albeit not functional, that directs proteins to the peroxisomes degradation. The actual function of Myocilin protein in the trabecular meshwork, in the retina, in the optic nerve head, in the lamina cribosa, in the cornea.. in almost all structures in of eye, is unknown. But it has been found to abound in about 36% of children suffering from Juvenile onset open angle glaucoma shows over-expression of MYOC/TIGR mutant gene. 4.6% of those with adult onset open angle glaucoma, with or without high IOP, had shown increased expression of the mutant MYOC. This mutant MYOC/TIGR is theorized to use its functional signaling sequence (in normal MYOC gene the signal sequence is not functional) to direct degradation of cell protein & hence subsequently cell degradation in the lamina cribosa & in the optic nerve fibres. Mutant MYOC/TIGR to cause neuropathy by cell protein degradation via peroxisome pathway.
Ishaemia of the optic nerve blood vessels, translaminar pressure of the eye, hereditory, prolonged use of topical dexmethasones, traumatic insults, inflamation of the optic nerve head etc are likely triggers that can cause mutations of both Optoneurin protein & the myocilin protein which are shown to be precursors to glaucomatous changes in the optic nerve head. I therefore agree that optic nerve head neuropathy in NTG is a physiological issue that manifests anatomically even in the absence of high intra-ocular pressure.
Thanks,
Dr Ezebuiroh Victor Okwudiri.

Note: There is no financial interest in this publication. thanks.