Cause Of Dominant Optic Atrophy Research Articles

Dominant optic atrophy: Culprit mitochondria in the optic nerve.

Dominant optic atrophy (DOA) is an inherited mitochondrial disease leading to specific degeneration of retinal ganglion cells (RGCs), thus compromising transmission of visual information from the retina to the brain. Usually, DOA starts during childhood and evolves to poor vision or legal blindness, affecting the central vision, whilst sparing the peripheral visual field. In 20% of cases, DOA presents as syndromic disorder, with secondary symptoms affecting neuronal and muscular functions. Twenty years ago, we demonstrated that heterozygous mutations in OPA1 are the most frequent molecular cause of DOA. Since then, variants in additional genes, whose functions in many instances converge with those of OPA1, have been identified by next generation sequencing. OPA1 encodes a dynamin-related GTPase imported into mitochondria and located to the inner membrane and intermembrane space. The many OPA1 isoforms, resulting from alternative splicing of three exons, form complex homopolymers that structure mitochondrial cristae, and contribute to fusion of the outer membrane, thus shaping the whole mitochondrial network. Moreover, OPA1 is required for oxidative phosphorylation, maintenance of mitochondrial genome, calcium homeostasis and regulation of apoptosis, thus making OPA1 the Swiss army-knife of mitochondria. Understanding DOA pathophysiology requires the understanding of RGC peculiarities with respect to OPA1 functions. Besides the tremendous energy requirements of RGCs to relay visual information from the eye to the brain, these neurons present unique features related to their differential environments in the retina, and to the anatomical transition occurring at the lamina cribrosa, which parallel major adaptations of mitochondrial physiology and shape, in the pre- and post-laminar segments of the optic nerve. Three DOA mouse models, with different Opa1 mutations, have been generated to study intrinsic mechanisms responsible for RGC degeneration, and these have further revealed secondary symptoms related to mitochondrial dysfunctions, mirroring the more severe syndromic phenotypes seen in a subgroup of patients. Metabolomics analyses of cells, mouse organs and patient plasma mutated for OPA1 revealed new unexpected pathophysiological mechanisms related to mitochondrial dysfunction, and biomarkers correlated quantitatively to the severity of the disease. Here, we review and synthesize these data, and propose different approaches for embracing possible therapies to fulfil the unmet clinical needs of this disease, and provide hope to affected DOA patients.

Drug repositioning as a therapeutic strategy for neurodegenerations associated with OPA1 mutations.

OPA1 mutations are the major cause of dominant optic atrophy (DOA) and the syndromic form DOA plus, pathologies for which there is no established cure. We used a ‘drug repurposing’ approach to identify FDA-approved molecules able to rescue the mitochondrial dysfunctions induced by OPA1 mutations. We screened two different chemical libraries by using two yeast strains carrying the mgm1I322M and the chim3P646L mutations, identifying 26 drugs able to rescue their oxidative growth phenotype. Six of them, able to reduce the mitochondrial DNA instability in yeast, have been then tested in Opa1 deleted mouse embryonic fibroblasts expressing the human OPA1 isoform 1 bearing the R445H and D603H mutations. Some of these molecules were able to ameliorate the energetic functions and/or the mitochondrial network morphology, depending on the type of OPA1 mutation. The final validation has been performed in patients’ fibroblasts, allowing to select the most effective molecules. Our current results are instrumental to rapidly translating the findings of this drug repurposing approach into clinical trial for DOA and other neurodegenerations caused by OPA1 mutations.

Red light provides partial protection against retinal ganglion cell degeneration in a mouse model of dominant optic atrophy through the activation of NFkB

PurposeMutations in OPA1 are the leading cause of dominant optic atrophy, a disease in which a progressive loss of retinal ganglion cells (RGCs) leads to blindness. In the B6;C3‐Opa1Q285STOP mouse, an Opa1 mutation causes a decrease in ATP production and a progressive loss in visual acuity, which coincides with pruning of the predominantly ON‐centre RGC dendrites. Explanting the retina, initiates further dendritic pruning. Red light has been shown to increase ATP production and provide neuroprotection. We hypothesised that 670 nm light can delay ex vivo dendritic pruning in the B6;C3‐Opa1Q285STOP mouse.MethodsWe therefore monitored the effects of 670 nm light (radiant exposure of 26.4 J/cm2) on RGC dendritic pruning in retinal explants from B6;C3‐Opa1Q285STOP mice, after 16 hours ex vivo.ResultsThe area under the Sholl curves, the peak of the Sholl curves and the total dendritic length of ON‐center RGCs showed statistically significant reductions by 28% (p<0.05), 27% (p<0.05) and 29% (p<0.05), respectively, from 0 to 16 hours ex vivo, with sham treatment but no statistically significant reductions were seen with 670 nm light treatment. An increase in the nuclear‐cytoplasmic ratio of transcription factor, NfkB, but not Nrf2, was found in the ganglion cell layer with 670 nm light treatment.ConclusionsThe results demonstrate the ability of 670 nm light to partially prevent ex vivo dendropathy in the B6;C3‐Opa1Q285STOP mouse retina, and that the transcription factor NfkB, but not Nrf2, plays a role. The findings suggests that 670 nm light may also delay the RGC dendritic pruning that occurs in vivo in the B6;C3‐Opa1Q285STOP mouse and ultimately provide neuroprotection against RGC degeneration in patients with dominant optic atrophy.

Antisense oligonucleotide therapy for splicing defects in OPA1‐related dominant optic atrophy

SummaryMutations in OPA1 are the main cause of dominant optic atrophy (DOA) and have also been implicated in a variety of syndromic neuropathies such as DOAplus or Behr‐like syndrome. We have recently discovered a disease‐causing deep intronic mutation (DIM) in OPA1 that induces a constitutive inclusion of a cryptic exon into OPA1 transcripts. As a potential therapeutic strategy we sought to correct mis‐splicing of the mutant pre‐mRNA by using antisense oligonucleotides targeting the cryptic acceptor splice site and the novel branch point created by the DIM, respectively. Transfection of patient‐derived primary dermal fibroblasts with AONs resulted in splice correction of the mutant pre‐mRNA in a time and concentration dependent manner. Maximal rescue efficacy of up ~55% was obtained with the cryptic acceptor splice site targeting AON. Peak efficacy of splice correction was observed at 4 days after treatment. However, significant effects were still seen 14 days post‐transfection in the proliferating cell culture. Western blot analysis revealed increased amounts of OPA1 protein with maximum amounts at ~3 days post‐treatment. In summary, we provide the first mutation‐specific rescue strategy for OPA1 deficiency using synthetic AONs.

OPA1-related disorders: Diversity of clinical expression, modes of inheritance and pathophysiology

Mutations in the Optic Atrophy 1 gene (OPA1) were first identified in 2000 as the main cause of Dominant Optic Atrophy, a disease specifically affecting the retinal ganglion cells and the optic nerve. Since then, an increasing number of symptoms involving the central, peripheral and autonomous nervous systems, with considerable variations of age of onset and severity, have been reported in OPA1 patients. This variety of phenotypes is attributed to differences in the effects of OPA1 mutations, to the mode of inheritance, which may be mono- or bi-allelic, and eventually to somatic mitochondrial DNA mutations. The diversity of the pathophysiological mechanisms involved in OPA1-related disorders is linked to the crucial role played by OPA1 in the maintenance of mitochondrial structure, genome and function. The neurological expression of these disorders highlights the importance of mitochondrial dynamics in neuronal processes such as dendritogenesis, axonal transport, and neuronal survival. Thus, OPA1-related disorders may serve as a paradigm in the wider context of neurodegenerative syndromes, particularly for the development of novel therapeutic strategies against these diseases.

Novel OPA1 missense mutation in a family with optic atrophy and severe widespread neurological disorder

To identify the underlying molecular genetic cause in a Czech family with optic atrophy, deafness, ptosis, ophthalmoplegia, polyneuropathy and ataxia transmitted as an autosomal dominant trait. Ophthalmological and neurological examination followed by molecular genetic analyses. Seven family members were clinically affected. There was a variable but progressive visual, hearing and neurological disability across the family as a whole. The majority of subjects presented with impairment of visual function and a variable degree of ptosis and/or ophthalmoplegia from the first to the third decade of life. Deafness, neuropathy and ataxia appeared later, in the third and fourth decade. Migraine, tachycardia, intention tremor, nystagmus and cervical dystonia were observed in isolated individuals. A significant overall feature was the high level of neurological disability leading to 3 of 4 members being unable to walk or stand unaided before the age of 60 years. A novel missense mutation c.1345A>C (p.Thr449Pro) in OPA1 segregating with the disease phenotype over three generations was detected. In silico analysis supported pathogenicity of the identified sequence variant. Our work expands the spectrum of mutation in OPA1, which may lead to severe multisystem neurological disorder. The molecular genetic cause of dominant optic atrophy in the Czech population is reported for the first time. We propose that regular cardiac follow-up in patients diagnosed with dominant optic atrophy and widespread neurological disease should be considered.

Loss of the Intermembrane Space Protein Mgm1/OPA1 Induces Swelling and Localized Constrictions along the Lengths of Mitochondria

Mgm1 is a member of the dynamin family of GTP-binding proteins. Mgm1 was first identified in yeast, where it affects mitochondrial morphology. The human homologue of Mgm1 is called OPA1. Mutations in the OPA1 gene are the prevailing cause of dominant optic atrophy, a hereditary disease in which progressive degeneration of the optic nerve can lead to blindness. Here we investigate the properties of the Mgm1/OPA1 protein in mammalian cells. We find that Mgm1/OPA1 is localized to the mitochondrial intermembrane space, where it is tightly bound to the outer surface of the inner membrane. Overexpression of wild type or mutant forms of the Mgm1/OPA1 protein cause mitochondria to fragment and, in some cases, cluster near the nucleus, whereas the loss of protein caused by small interfering RNA (siRNA) leads to dispersal of mitochondrial fragments throughout the cytosol. The cristae of these fragmented mitochondria are disorganized. At early time points after transfection with Mgm1/OPA1 siRNA, the mitochondria are not yet fragmented. Instead, the mitochondria swell and stretch, after which they form localized constrictions similar to the mitochondrial abnormalities observed during the early stages of apoptosis. These abnormalities might be the earliest effects of losing Mgm1/OPA1 protein.