**7. Conclusions and future directions**

Optineurin functions as an adaptor protein and thereby plays a crucial role in several functions including vesicle trafficking in the secretory and recycling pathways, NF-κB signalling, control of mitosis, Golgi organization, autophagy and antiviral signalling. The relationship between these different functions of optineurin is not clear. Since optineurin is an adaptor protein, mutations in it can lead to altered interactions with other proteins impairing its normal cellular functions. Identifying the functions that are affected by disease-associated mutations of optineurin is a major challenge towards understanding the molecular mechanisms of etiopa‐ thogenesis of neurodegenerative disease like glaucoma. Presently, our understanding of the molecular mechanisms of functional defects caused by E50K mutation, the best studied mutant, is far from complete. Several questions remain to be answered. How does E50K mutation cause a block in autophagy? Does E50K mutant cause inhibition of secretion of neutrophins/survival factors? Is Rab8 involved in this process? Does impaired transferrin receptor trafficking or function contribute to E50K-induced RGC death? How does H486R mutant cause glaucoma? Does it cause autoimmune defects by impairing the function of CYLD? How do other mutants of optineurin alter its function? Why some mutations cause ALS and others cause glaucoma? Are mutations of optineurin also prevalent in other neuro‐ degenerative diseases? Is interaction of optineurin or its mutants altered with huntingtin or its mutants? If so, what is its relevance for Huntington's disease and glaucoma? Role of various mutants of optineurin in affecting known functions of optineurin needs to be examined. This would help in understanding the molecular mechanisms of pathogenesis of glaucoma and other neurodegenerative diseases. Most of the optineurin mutants do not directly induce death of RGC-5 cells upon overexpression, indicating, therefore, that these optineurin mutations might cause glaucoma by indirect mechanisms involving defects in other cells/tissues (Figure 6]. Survival of RGCs is influenced by other accessory cells like glial cells. Role of optineurin mutants in autoimmunity and glial cell activation needs to be explored.

Functional defects caused by mutations in optineurin in cells other than RGC, especially glial cells could also be relevant for glaucoma pathogenesis. However, molecular mechanism of such effects and relevance to glaucoma needs to be established. Transgenic and knockout animal models are needed to understand the complex and diverse mechanisms involved in

Functional Defects Caused by Glaucoma – Associated Mutations in Optineurin

http://dx.doi.org/10.5772/52692

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RGC, Retinal ganglion cells; IOP, Intraocular pressure; POAG, Primary open angle glaucoma; JOAG, Juvenile open angle glaucoma; NTG, Normal tension glaucoma; ACG, Angle closure glaucoma; TIGR, trabecular meshwork inducible glucocorticoid response; WDR36, WD repeat 36; CYP1B1, cytochrome p4501B1; NTF3/4, neurotrophin3/4; ALS, amyotrophic lateral sclerosis; UBD, ubiquitin-binding domain; GLUT4, glucose transporter member 4; EGF, epidermal growth factor; GAP, GTPase activating protein; NF-κB, Nuclear factor κB; IκB, inhibitor of kB; TNFα, tumor necrosis factor α; TNFR1, tumor necrosis factor Receptor1; TRADD- TNFR1-associated DEATH domain protein; TRAF2, TNF receptor associated factor 2; RIP, receptor interacting protein; IKK, IκB kinase; NEMO, NF-κB essential modifier; UXT, ubiquitously-expressed transcript; LC3- microtubule-associated protein 1 light chain 3; CTNF, ciliary neurotrophic factor; Plk1, Polo-like kinase; MYPT1, myosin phosphatase target subunit 1; Cdk1, cyclin dependent kinase 1; IRF3, Interferon regulatory factor 3; TBK1, TANK binding kinase; MDA5, melanoma differentiation associated gene 5; TRIF, TIR-domain-containing adapter-inducing interferon-β; ROS, reactive oxygen species; RIG1, retinoic acid inducible

This work was supported by a grant to GS from the Department of Biotechnology, Government of India. GS gratefully acknowledges the Department of Science and Technology, Government of India for J C Bose National Fellowship. VV is recipient of a Senior Research Fellowship from

, Vipul Vaibhava and Ananthamurthy Nagabhushana

Centre for Cellular and Molecular Biology, Council of Scientific and Industrial Research,

the pathogenesis of glaucoma and ALS caused by mutations in optineurin.

**Abbreviations**

gene 1.

**Acknowledgements**

the CSIR, New Delhi, India.

**Author details**

Hyderabad, India

Ghanshyam Swarup\*

\*Address all correspondence to: gshyam@ccmb.res.in

**Figure 6.** Overview of role of optineurin mutations in causing Glaucoma.

Functional defects caused by mutations in optineurin in cells other than RGC, especially glial cells could also be relevant for glaucoma pathogenesis. However, molecular mechanism of such effects and relevance to glaucoma needs to be established. Transgenic and knockout animal models are needed to understand the complex and diverse mechanisms involved in the pathogenesis of glaucoma and ALS caused by mutations in optineurin.
