Electrophysiological and Histologic Assessment of Retinal Ganglion Cell Fate in a Mouse Model for<i>OPA1</i>-Associated Autosomal Dominant Optic Atrophy

Heiduschka, Peter; Schnichels, Sven; Fuhrmann, Nico; Hofmeister, Sabine; Schraermeyer, Ulrich; Wissinger, Bernd; Alavi, Marcel V.

doi:10.1167/iovs.09-3606

Cited by 63 publications

(51 citation statements)

References 37 publications

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“…Disturbances in transmission through this pathway are manifested in neurodegenerative diseases, such as ALS, multiple sclerosis, optic atrophies, and several retinopathies (107)(108)(109)(110). We examined cone and rod photoreceptor functions by light-and dark-adapted ERGs and transmission through the visual pathway, including retinal ganglion cells, in VEPs.…”

Section: Disturbances In Visual Evoked Potentials In Tgranbp2mentioning

confidence: 99%

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Cho

Patil

Senda

et al. 2014

Journal of Biological Chemistry

157

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Background: Cyclophilins harbor ill-defined chaperone and prolyl isomerase activities toward physiological substrates. Results: Nonoverlapping chaperone or prolyl isomerase activity loss of Ran-binding protein 2 (Ranbp2) cyclophilin domain triggers unique impairments of proteostasis in distinct cell types and ubiquitin-proteasome system. Conclusion: Ranbp2 cyclophilin subdomains present discriminating physiological activities toward substrates or regulation of ubiquitin-proteasome system. Significance: Ranbp2-mediated mechanistic links in proteostasis with physiological and therapeutic relevance are uncovered.The immunophilins, cyclophilins, catalyze peptidyl cis-trans prolyl-isomerization (PPIase), a rate-limiting step in protein folding and a conformational switch in protein function. Cyclophilins are also chaperones. Noncatalytic mutations affecting the only cyclophilins with known but distinct physiological substrates, the Drosophila NinaA and its mammalian homolog, cyclophilin-B, impair opsin biogenesis and cause osteogenesis imperfecta, respectively. However, the physiological roles and substrates of most cyclophilins remain unknown. It is also unclear if PPIase and chaperone activities reflect distinct cyclophilin properties. To elucidate the physiological idiosyncrasy stemming from potential cyclophilin functions, we generated mice lacking endogenous Ran-binding protein-2 (Ranbp2) and expressing bacterial artificial chromosomes of Ranbp2 with impaired C-terminal chaperone and with (Tg-Ranbp2 WT-HA ) or without PPIase activities (Tg-Ranbp2 R2944A-HA ). The transgenic lines exhibit unique effects in proteostasis. Either line presents selective deficits in M-opsin biogenesis with its accumulation and aggregation in cone photoreceptors but without proteostatic impairment of two novel Ranbp2 cyclophilin partners, the cytokine-responsive effectors, STAT3/STAT5. Peptidyl cis-trans-prolyl isomerization is a rate-limiting step in protein folding (1-3). The catalysis of the cis-trans interconversion of the peptidyl-prolyl isomers is catalyzed by peptidylprolyl cis-trans isomerases (PPIase) 5 (4 -6). PPIases compose three families of structurally unrelated proteins, the cyclophilins (CyP), FK506-binding proteins (FKBP), and parvulins (7). * This work was supported, in whole or in part, by National Institutes of Health Grants EY019492, GM083165, and GM083165-03S1 (to P. A. F.), 2P30-EY005722 (to Duke University Eye Center), and 5P30NS061789 (to Duke Neurotransgenic Laboratory). This work was also supported by the Foundation Fighting CyPs and FKBPs are designated also as immunophilins, because they mediate immunosuppression (8,9). This effect is achieved by a gain-of-function mechanism upon binding of the immunosuppressive metabolites, cyclosporin A (CsA) or FK506, to the PPIase active site and formation of a ternary complex with the serine/threonine phosphatase, calcineurin, whose sequestration and inhibition prevents the dephosphorylation and activation of the nuclear factor for activation of T-cells (9 -12). Howe...

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Section: Disturbances In Visual Evoked Potentials In Tgranbp2mentioning

confidence: 99%

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Cho

Patil

Senda

et al. 2014

Journal of Biological Chemistry

157

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“…OPA1 is another reported human NTG-causing gene. OPA1 gene-mutated mice were showed with loss of RGCs, optic nerve atrophy, and abnormal visually evoked potential 23. WD repeat-containing protein 36 (WDR36)24 has been identified as being associated with POAG 29.…”

Section: The Basic Research and Clinical Investigations Of Ntgmentioning

confidence: 99%

The current research status of normal tension glaucoma

Mi¹,

Yuan²,

So³

2014

CIA

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Normal tension glaucoma (NTG) is a progressive optic neuropathy that mimics primary open-angle glaucoma, but lacks the findings of elevated intraocular pressure or other mitigating factors that can lead to optic neuropathy. The present review summarized the causes, genetics, and mechanisms underlying NTG in both animal models and human patients. We also proposed that the neurovascular unit is a therapeutic target for NTG management.

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“…OPA1 has recently been identified as a disease gene for autosomal dominant optic atrophy (ADOA). The disease has a very similar clinical phenotype to LHON and is specifically expressed in retinal ganglion and nerve cells (Heiduschka et al 2010;Ju et al 2005;Pesch et al 2004). While there have been limited studies of PARL expression in the retina, expression of Rhomboid-7 (rho-7) (an ortholog of human PARL) has been shown to cause severe neurodegeneration and reduced the lifespan in mutant D. melanogaster (Lessing and Bonini 2009;McQuibban et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand

et al. 2010

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Leber hereditary optic neuropathy (LHON) is the most common mitochondrially inherited disease causing blindness, preferentially in young adult males. Most of the patients carry the G11778A mitochondrial DNA (mtDNA) mutation. However, the marked incomplete penetrance and the gender bias indicate some additional genetic and/or environmental factors to disease expression. Herein, we first conducted a genome-wide linkage scan with 400 microsatellite markers in 9 large Thai LHON G11778A pedigrees. Using an affecteds-only nonparametric linkage analysis, 4 regions on chromosomes 3, 12, 13 and 18 showed Zlr scores greater than 2 (P < 0.025), which is consistently significant across several linkage statistics. The most suggestive marker D3S1565 (Zlr > 2 in 10 of 16 allele sharing models tested) was then expanded to include the region 3q26.2-3q28 covering SLC7A14 (3q26.2), MFN1 (3q26.32), MRPL47 (3q26.33), MCCC1 (3q27.1), PARL (3q27.1) and OPA1 (3q28-q29). All of these candidate genes were selected from the Maestro database and had known to be localized in mitochondria. Sixty tag SNPs were genotyped in 86 cases, 211 of their relatives and 32 unrelated Thai controls, by multiplex-PCR-based Invader assay. Analyses using a powerful association testing tool that adjusts for relatedness (the M(QLS) statistic) showed the most evidence of association between two SNPs, rs3749446 and rs1402000 (located in PARL presenilins-associated rhomboid-like) and LHON expression (both P = 8.8 x 10(-5)). The mitochondrial PARL protease has been recently known to play a role with a dynamin-related OPA1 protein in preventing apoptotic events by slowing down the release of cytochrome c out of mitochondrial cristae junctions. Moreover, PARL is required to activate the intramembranous proteolyses resulting in the degradation of an accumulated pro-apoptotic protein in the outer mitochondrial membrane. Under these circumstances, variants of PARL are suggested to influence cell death by apoptosis which has long been believed to intrigue the neurodegeneration of LHON.

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Electrophysiological and Histologic Assessment of Retinal Ganglion Cell Fate in a Mouse Model forOPA1-Associated Autosomal Dominant Optic Atrophy

Cited by 63 publications

References 37 publications

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

Differential Loss of Prolyl Isomerase or Chaperone Activity of Ran-binding Protein 2 (Ranbp2) Unveils Distinct Physiological Roles of Its Cyclophilin Domain in Proteostasis

The current research status of normal tension glaucoma

Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand

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