“…34 The Opa1 enu/+ mouse is a true model for ADOA 5, 8 and intriguingly, it also displays subclinical neurological and metabolic impairments. 7 Consistent with these results, we found that Opa1 enu/+ mice had a greater RGC loss than wild-type control mice. Further, loss of RGCs in Opa1 enu/+ mice is not uniform, which is in agreement with the human pathology of ADOA.…”
Section: Discussionsupporting
confidence: 87%
“…3, 4 Emerging evidence suggests that mice carrying heterozygous mutations in the murine OPA1 gene resemble the human disease phenotype and thus can be regarded as true models for ADOA. 5, 6, 7 Studies on these models provided further evidence for a causative connection between OPA1 mutations and ascending RGC death, making ADOA a true neurodegenerative disease. 8 Nevertheless, the functional role of OPA1 as well as the signaling mechanism between OPA1 mutations and RGC death in ADOA remains unknown.…”
Glutamate excitotoxicity leads to fragmented mitochondria in neurodegenerative diseases, mediated by nitric oxide and S-nitrosylation of dynamin-related protein 1, a mitochondrial outer membrane fission protein. Optic atrophy gene 1 (OPA1) is an inner membrane protein important for mitochondrial fusion. Autosomal dominant optic atrophy (ADOA), caused by mutations in OPA1, is a neurodegenerative disease affecting mainly retinal ganglion cells (RGCs). Here, we showed that OPA1 deficiency in an ADOA model influences N-methyl-D-aspartate (NMDA) receptor expression, which is involved in glutamate excitotoxicity and oxidative stress. Opa1enu/+ mice show a slow progressive loss of RGCs, activation of astroglia and microglia, and pronounced mitochondrial fission in optic nerve heads as found by electron tomography. Expression of NMDA receptors (NR1, 2A, and 2B) in the retina of Opa1enu/+ mice was significantly increased as determined by western blot and immunohistochemistry. Superoxide dismutase 2 (SOD2) expression was significantly decreased, the apoptotic pathway was activated as Bax was increased, and phosphorylated Bad and BcL-xL were decreased. Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics.
“…34 The Opa1 enu/+ mouse is a true model for ADOA 5, 8 and intriguingly, it also displays subclinical neurological and metabolic impairments. 7 Consistent with these results, we found that Opa1 enu/+ mice had a greater RGC loss than wild-type control mice. Further, loss of RGCs in Opa1 enu/+ mice is not uniform, which is in agreement with the human pathology of ADOA.…”
Section: Discussionsupporting
confidence: 87%
“…3, 4 Emerging evidence suggests that mice carrying heterozygous mutations in the murine OPA1 gene resemble the human disease phenotype and thus can be regarded as true models for ADOA. 5, 6, 7 Studies on these models provided further evidence for a causative connection between OPA1 mutations and ascending RGC death, making ADOA a true neurodegenerative disease. 8 Nevertheless, the functional role of OPA1 as well as the signaling mechanism between OPA1 mutations and RGC death in ADOA remains unknown.…”
Glutamate excitotoxicity leads to fragmented mitochondria in neurodegenerative diseases, mediated by nitric oxide and S-nitrosylation of dynamin-related protein 1, a mitochondrial outer membrane fission protein. Optic atrophy gene 1 (OPA1) is an inner membrane protein important for mitochondrial fusion. Autosomal dominant optic atrophy (ADOA), caused by mutations in OPA1, is a neurodegenerative disease affecting mainly retinal ganglion cells (RGCs). Here, we showed that OPA1 deficiency in an ADOA model influences N-methyl-D-aspartate (NMDA) receptor expression, which is involved in glutamate excitotoxicity and oxidative stress. Opa1enu/+ mice show a slow progressive loss of RGCs, activation of astroglia and microglia, and pronounced mitochondrial fission in optic nerve heads as found by electron tomography. Expression of NMDA receptors (NR1, 2A, and 2B) in the retina of Opa1enu/+ mice was significantly increased as determined by western blot and immunohistochemistry. Superoxide dismutase 2 (SOD2) expression was significantly decreased, the apoptotic pathway was activated as Bax was increased, and phosphorylated Bad and BcL-xL were decreased. Our results conclusively demonstrate that not only glutamate excitotoxicity and/or oxidative stress alters mitochondrial fission/fusion, but that an imbalance in mitochondrial fission/fusion in turn leads to NMDA receptor upregulation and oxidative stress. Therefore, we propose a new vicious cycle involved in neurodegeneration that includes glutamate excitotoxicity, oxidative stress, and mitochondrial dynamics.
“…The majority (60–70 %) of patients with DOA harbour pathogenic mutations in the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein with multifunctional properties [4, 47]. Over 250 OPA1 mutations have been reported and these can be grouped into two major categories depending on whether they are predicted to cause disease due to haploinsufficiency (deletions, insertions, splice site and nonsense mutations) or a possible dominant-negative mechanism (missense mutations) [50, 53].…”
“…Among the Opa1 mouse models that have been established, there is also a suggestion that some of the mutant mice can develop extraocular features analogous to the more severe syndromic “plus” phenotypes observed in a proportion of patients with DOA. In addition to inner retinal and optic nerve degeneration, more widespread neuropathological and psychophysical abnormalities have been noted in subgroups of Opa1
+ / − mutant mice, including enlarged lateral ventricles within the brain, disorganised myofibres in skeletal and cardiac muscle, locomotive and ataxic gait disturbance, and decreased auditory brainstem responses [4, 40, 120]. Fig.…”
Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1625-2) contains supplementary material, which is available to authorized users.
“…These heterozygous mice, with a 50% reduction of Opa1, replicate the human clinical condition, with a slowly progressive bilateral optic neuropathy associated with the loss of retinal ganglion cells (RGCs). The first two Opa1 +/− mouse models, i.e., the c.1065 + 5GNA and c.1051CNT mouse models, display a DOA phenotype with mild extraocular features, such as subtle neurological and metabolic abnormalities (Alavi et al, 2009), late-onset cardiomyopathy (Chen et al, 2012), and increased endurance (Caffin et al, 2013). The third Opa1 +/− mouse model, i.e., the c.2708delTTAG mouse model, presents a multisystemic neurodegenerative DOA+ phenotype associating deafness, encephalo-myopathy, peripheral neuropathy and ataxia (Sarzi et al, 2012).…”
Section: Diversity Of the Clinical Spectrum Of Opa1 Mutationsmentioning
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