Key molecular pathways affected by glaucoma pathology: is predictive diagnosis possible?

Abstract

Prediction and prevention of glaucoma. Neurodegenerative eye disease glaucoma is the second leading cause of blindness with estimated 67 million patients worldwide. Molecular pathomechanisms of glaucoma demonstrate both a considerable overlap with and remarkable particularities compared to other neurodegenerative disorders e.g. Alzheimer's disease. Identification of pathology-specific biomarker-sets is essential to develop advanced diagnostic approaches and personalised patients' treatment. Subcellular imaging and expression patterns in blood as the reliable platform for early/predictive glaucoma diagnosis. Following key pathways are affected in glaucoma pathology: stress response, apoptosis and DNA-repair, adhesion, blood-brain-barrier-breakdown, tissue remodelling, transcription regulation, multidrug resistance and energy metabolism.

Fig. 1

Characteristic degenerative tissue remodelling by glaucomatous damage [5]

Fig. 2

Risk factors in glaucoma and measurement of intraocular pressure (IOP) [5]

Fig. 3

Although increased IOP is a well-known risk factor, the IOP values of normal-tension glaucoma patients are within statistical norm

Fig. 4

Protein expression patterns characteristic for circulating leucocytes of glaucoma patients [30]. a. 2D-PAGE images of differential gene expression patterns in circulating leucocytes of glaucoma patients versus controls with particular changes marked. b. The scheme represents summarised results from the evaluation of comparative 2D-PAGE images. 132 protein spots were constantly present in all control images, whereby 75 spots were expressed at the same level. 133 protein spots were constantly present in patient images, whereby 52 spots were expressed at the same level. 17 proteins represent the overlap between 75 and 52 protein spots. Thirty spots were present only in the control group whereas 14 spots were present only in the patient group; all spots were detectable only in single images and, therefore, were not included in the above 133 and 132 pools. c. Quantitative analysis of 2D-PAGE images: among 75 and 52 conserved protein spots in the control and patient groups, respectively, 17 overlapping protein spots were found to be conserved for members of the same group. Corresponding expression levels in the control group are taken as standard (=1). 9 proteins have been identified as given in the table

Fig. 5

a. Principle of “gene hunting” by the “Subtractive Hybridisation” [1, 34]. Each mRNA-pool consists of individual gene transcripts, which undergo a comparison by hybridisation of identical (complementary) parts. The subtraction results in identification of non-complementary transcripts differentially expressed in two pools of comparison; the technology enables a consideration of both qualitative (present or absent) and quantitative (amount of copies per unit weight of mRNA in the corresponding pool) differences b. Consequent quantification of the target transcripts (mRNA “Dot-Blot”-analysis), further provided a strong indication for increased stress, apoptosis, protein damage and axonal damage as well as insufficient DNA-repair and altered drug-sensitivity in patients with glaucoma compared to the control group