<i>TBK1</i>and Flanking Genes in Human Retina

Fingert, John H.; Darbro, Benjamin W.; Qian, Qining; Rheeden, Richard Van; Miller, Kathy Ann; Riker, Megan; Solivan-Timpe, Frances; Roos, Ben R.; Robin, Alan L.; Mullins, Robert F.

doi:10.3109/13816810.2013.768674

Cited by 16 publications

(12 citation statements)

References 23 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, duplication of TBK1 gene locus has been reported in NTG, although no disease-causing mutations in TBK1 have been reported [ 6 ]. Duplication of TBK1 gene locus in NTG patients was associated with increased transcript levels of TBK1 in retina [ 6 , 68 ]. Gene duplication and increased transcript levels could probably result in increased protein level and activity.…”

Section: Discussionmentioning

confidence: 99%

A Glaucoma-Associated Variant of Optineurin, M98K, Activates Tbk1 to Enhance Autophagosome Formation and Retinal Cell Death Dependent on Ser177 Phosphorylation of Optineurin

et al. 2015

View full text Add to dashboard Cite

Certain missense mutations in optineurin/OPTN and amplification of TBK1 are associated with normal tension glaucoma. A glaucoma-associated variant of OPTN, M98K, induces autophagic degradation of transferrin receptor (TFRC) and death in retinal cells. Here, we have explored the role of Tbk1 in M98K-OPTN-induced autophagy and cell death, and the effect of Tbk1 overexpression in retinal cells. Cell death induced by M98K-OPTN was dependent on Tbk1 as seen by the effect of Tbk1 knockdown and blocking of Tbk1 activity by a chemical inhibitor. Inhibition of Tbk1 also restores M98K-OPTN-induced transferrin receptor degradation. M98K-OPTN-induced autophagosome formation, autophagy and cell death were dependent on its phosphorylation at S177 by Tbk1. Knockdown of OPTN reduced starvation-induced autophagosome formation. M98K-OPTN expressing cells showed higher levels of Tbk1 activation and enhanced phosphorylation at Ser177 compared to WT-OPTN expressing cells. M98K-OPTN-induced activation of Tbk1 and its ability to be phosphorylated better by Tbk1 was dependent on ubiquitin binding. Phosphorylated M98K-OPTN localized specifically to autophagosomes and endogenous Tbk1 showed increased localization to autophagosomes in M98K-OPTN expressing cells. Overexpression of Tbk1 induced cell death and caspase-3 activation that were dependent on its catalytic activity. Tbk1-induced cell death possibly involves autophagy, as shown by the effect of Atg5 knockdown, and requirement of autophagic function of OPTN. Our results show that phosphorylation of Ser177 plays a crucial role in M98K-OPTN-induced autophagosome formation, autophagy flux and retinal cell death. In addition, we provide evidence for cross talk between two glaucoma associated proteins and their inter-dependence to mediate autophagy-dependent cell death.

show abstract

Section: Discussionmentioning

confidence: 99%

A Glaucoma-Associated Variant of Optineurin, M98K, Activates Tbk1 to Enhance Autophagosome Formation and Retinal Cell Death Dependent on Ser177 Phosphorylation of Optineurin

et al. 2015

View full text Add to dashboard Cite

show abstract

“…22 Second, TBK1 is specifically expressed in the ganglion cells and the nerve fiber layer of the human retina, which are involved in the pathogenesis of glaucoma. 15,23 Third, OPTN binds the TBK1 protein, particularly in the presence of the recurrent severe glaucoma-causing mutation E50K in the OPTN gene. 24 Interestingly, 3 known normal-tension glaucoma genes (TBK1, OPTN, and TLR4) each encode proteins that directly interact with each other in a biological pathway that activates autophagy, 25,26 a process by which intracellular materials (eg, proteins, organelles, or pathogens) are degraded.…”

mentioning

confidence: 99%

Copy Number Variations of TBK1 in Australian Patients With Primary Open-Angle Glaucoma

Awadalla¹,

Fingert²,

Roos³

et al. 2015

American Journal of Ophthalmology

Self Cite

View full text Add to dashboard Cite

PURPOSE To investigate the presence of TBK1 copy number variations in a large, well-characterized Australian cohort of patients with glaucoma comprising both normal-tension glaucoma and high-tension glaucoma cases. DESIGN A retrospective cohort study. METHODS DNA samples from patients with normal-tension glaucoma and high-tension glaucoma and unaffected controls were screened for TBK1 copy number variations using real-time quantitative polymerase chain reaction. Samples with additional copies of the TBK1 gene were further tested using custom comparative genomic hybridization arrays. RESULTS Four out of 334 normal-tension glaucoma cases (1.2%) were found to carry TBK1 copy number variations using quantitative polymerase chain reaction. One extra dose of the TBK1 gene (duplication) was detected in 3 normal-tension glaucoma patients, while 2 extra doses of the gene (triplication) were detected in a fourth normal-tension glaucoma patient. The results were further confirmed by custom comparative genomic hybridization arrays. Further, the TBK1 copy number variation segregated with normal-tension glaucoma in the family members of the probands, showing an autosomal dominant pattern of inheritance. No TBK1 copy number variations were detected in 1045 Australian patients with high-tension glaucoma or in 254 unaffected controls. CONCLUSION We report the presence of TBK1 copy number variations in our Australian normal-tension glaucoma cohort, including the first example of more than 1 extra copy of this gene in glaucoma patients (gene triplication). These results confirm TBK1 to be an important cause of normal-tension glaucoma, but do not suggest common involvement in high-tension glaucoma.

show abstract

“…We previously demonstrated that TBK1 is specifically localized to the retinal ganglion cells in the human retina (27,61). In this report, we identify native mouse Tbk1 in the inner and outer nuclear layer cells as well as in the retinal ganglion cells in the retinae of wild-type and Tg-TBK1 mice.…”

Section: Discussionmentioning

confidence: 60%

TransgenicTBK1mice have features of normal tension glaucoma

et al. 2016

Self Cite

View full text Add to dashboard Cite

Duplication of the TBK1 gene is associated with 1-2% of normal tension glaucoma, a common cause of vision loss and blindness that occurs without grossly abnormal intraocular pressure. We generated a transgenic mouse that has one copy of the human TBK1 gene (native promoter and gene structure) incorporated into the mouse genome (Tg-TBK1). Expression of the TBK1 transgene in the retinae of these mice was demonstrated by real-time PCR. Using immunohistochemistry TBK1 protein was predominantly localized to the ganglion cell layer of the retina, the cell type most affected by glaucoma. More intense TBK1 labelling was detected in the retinal ganglion cells (RGCs) of Tg-TBK1 mice than in wild-type littermates. Tg-TBK1 mice exhibit the cardinal sign of glaucoma, a progressive loss of RGCs. Hemizygous Tg-TBK1 mice (with one TBK1 transgene per genome) had a 13% loss of RGCs by 18 months of age (P = 1.5 × 10-8). Homozygous Tg-TBK1 mice had 7.6% fewer RGCs than hemizygous Tg-TBK1 mice and 20% fewer RGCs than wild-type mice (P = 1.9 × 10-5) at 6 months of age. No difference in intraocular pressures was detected between Tg-TBK1 mice and wild-type littermates as they aged (P > 0.05). Tg-TBK1 mice with extra doses of the TBK1 gene recapitulate the phenotype of normal tension glaucoma in human patients with a TBK1 gene duplication. Together, these studies confirm the pathogenicity of the TBK1 gene duplication in human glaucoma and suggest that excess production of TBK1 kinase may have a role in the pathology of glaucoma.

show abstract

TBK1and Flanking Genes in Human Retina

Cited by 16 publications

References 23 publications

A Glaucoma-Associated Variant of Optineurin, M98K, Activates Tbk1 to Enhance Autophagosome Formation and Retinal Cell Death Dependent on Ser177 Phosphorylation of Optineurin

A Glaucoma-Associated Variant of Optineurin, M98K, Activates Tbk1 to Enhance Autophagosome Formation and Retinal Cell Death Dependent on Ser177 Phosphorylation of Optineurin

Copy Number Variations of TBK1 in Australian Patients With Primary Open-Angle Glaucoma

TransgenicTBK1mice have features of normal tension glaucoma

Contact Info

Product

Resources

About