Optic atrophy 1 controls human neuronal development by preventing aberrant nuclear DNA methylation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE117976 | GEO | 2020/04/30
REPOSITORIES: GEO
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Project description:Optic atrophy 1 (OPA1), a GTPase at the inner mitochondrial membrane involved in regulating mitochondrial fusion, stability, and energy output, is known to be crucial for neural development: Opa1 heterozygous mice show abnormal brain development, and inactivating mutations in OPA1 are linked to human neurological disorders. Here, we used genetically modified human embryonic and patient-derived induced pluripotent stem cells and reveal that OPA1 haploinsufficiency leads to aberrant nuclear DNA methylation and significantly alters the transcriptional circuitry in neural progenitor cells (NPCs). For instance, expression of the forkhead box G1 transcription factor, which is needed for GABAergic neuronal development, is repressed in OPA1+/- NPCs. Supporting this finding, OPA1+/- NPCs cannot give rise to GABAergic interneurons, whereas formation of glutamatergic neurons is not affected. Taken together, our data reveal that OPA1 controls nuclear DNA methylation and expression of key transcription factors needed for proper neural cell specification.
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Project description:Optic atrophy 1 controls human neuronal development by preventing aberrant nuclear DNA methylation
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2023-10-10 | GSE218907 | GEO
Project description:Dysfunctions in mitochondria dynamics and metabolism are common pathological processes associated with Parkinson’s disease (PD). Recently, it was shown that an inherited form of PD and dementia is caused by new mutations in the OPA1 gene, which encodes for a key player of mitochondrial fusion and structure. iPSC-derived neural cells from these patients exhibited severe mitochondrial fragmentation, respiration impairment, ATP deficits and heightened oxidative stress. Reconstitution of normal levels of OPA1 in PD-derived neural cells normalized mitochondria morphology and function. OPA1 mutated neuronal cultures showed reduced survival in vitro. Intriguingly, selective inhibition of necroptosis effectively rescued this survival deficit. Additionally, dampening necroptosis in MPTP treated mice protected from DA neuronal cell loss. This human iPSC-based model captures both the early pathological events in OPA1 mutant neural cells and the beneficial effects of blocking necroptosis, highlighting this cell death process as a promising therapeutic target for PD.
2019-01-16 | GSE109228 | GEO
Project description:During human pregnancy, placental trophoblasts differentiate and syncytialize into syncytiotrophoblasts that sustain progesterone production [1]. This process is accompanied by mitochondrial fragmentation and cristae remodeling [2], two facets of mitochondrial apoptosis, whose molecular mechanisms and functional consequences on steroidogenesis are unclear. Here we show that the mitochondria-shaping protein Optic atrophy 1 (Opa1) controls efficiency of steroidogenesis. During syncytialization of trophoblast BeWo cells, levels of the profission mitochondria-shaping protein Drp1 increase, and those of Opa1 and mitofusin (Mfn) decrease, leading to mitochondrial fragmentation and cristae remodeling. Manipulation of the levels of Opa1 reveal an inverse relationship with the efficiency of steroidogenesis in trophoblasts and in mouse embryonic fibroblasts where the mitochondrial steroidogenetic pathway has been engineered. In an in vitro assay, accumulation of cholesterol is facilitated in the inner membrane of isolated mitochondria lacking Opa1. Thus, Opa1-dependent inner membrane remodeling controls efficiency of steroidogenesis.
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Project description:Astrocytes negatively impact neuronal development in a range of neurodevelopmental disorders (NDs), however how they do this, and if mechanisms are shared across multiple disorders, is not known. We developed an in vitro system to ask how astrocyte protein secretion and gene expression change in 3 genetic NDs. This identified disorder specific changes, as well as core proteins that are increased in release in all 3 NDs. ND astrocytes increase release of Igfbp2, and blocking Igfbp2 partially rescues the neurite outgrowth inhibitory effects of Rett Syndrome astrocytes. We identified that ND astrocytes upregulate release of Bmp6, which acts on astrocytes themselves and is upstream of astrocyte secretion changes in NDs. Blocking Bmp signaling in Fragile X Syndrome astrocytes reverses the inhibitory effects of FXS astrocytes on neuronal development. We provide a resource of astrocyte secreted proteins in health and NDs, as well as novel targets for intervention in diverse NDs.
2022-07-11 | PXD015996 | Pride
Project description:Optic Atrophy 1 (OPA1) gene mutations cause diseases ranging from isolated dominant optic atrophy (DOA) to various multisystemic disorders. OPA1, a large GTPase belonging to the dynamin family, is involved in mitochondrial network dynamics. The majority of OPA1 mutations encodes truncated forms of the protein and causes DOA through haploinsufficiency, whereas missense OPA1 mutations are predicted to cause disease through deleterious dominant-negative mechanisms. We used 3D imaging and biochemical analysis to explore autophagy and mitophagy in fibroblasts from seven patients harbouring OPA1 mutations. We report new genotype-phenotype correlations between various types of OPA1 mutation and mitophagy. Fibroblasts bearing dominant-negative OPA1 mutations showed increased autophagy and mitophagy in response to uncoupled oxidative phosphorylation. In contrast, OPA1 haploinsufficiency was correlated with a substantial reduction in mitochondrial turnover and autophagy, unless subjected to experimental mitochondrial injury. Our results indicate distinct alterations of mitochondrial physiology and turnover in cells with OPA1 mutations, suggesting that the level and profile of OPA1 may regulate the rate of mitophagy.
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Project description:DEFINITION OF THE DISEASE: Dominant Optic Atrophy (DOA) is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC) and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain.The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world.DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts.Two genes (OPA1, OPA3) encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8) are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7) are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis.Patients are usually diagnosed during their early childhood, because of bilateral, mild, otherwise unexplained visual loss related to optic discs pallor or atrophy, and typically occurring in the context of a family history of DOA. Optical Coherence Tomography further discloses non-specific thinning of retinal nerve fiber layer, but a normal morphology of the photoreceptors layers. Abnormal visual evoked potentials and pattern ERG may also reflect the dysfunction of the RGCs and their axons. Molecular diagnosis is provided by the identification of a mutation in the OPA1 gene (75% of DOA patients) or in the OPA3 gene (1% of patients).Visual loss in DOA may progress during puberty until adulthood, with very slow subsequent chronic progression in most of the cases. On the opposite, in DOA patients with associated extra-ocular features, the visual loss may be more severe over time.To date, there is no preventative or curative treatment in DOA; severely visually impaired patients may benefit from low vision aids. Genetic counseling is commonly offered and patients are advised to avoid alcohol and tobacco consumption, as well as the use of medications that may interfere with mitochondrial metabolism. Gene and pharmacological therapies for DOA are currently under investigation.
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Project description:Mitochondrial dysfunction and mitophagy are often hallmarks of neurodegenerative diseases such as autosomal dominant optic atrophy (ADOA) caused by mutations in the key mitochondrial dynamics protein optic atrophy 1 (Opa1). However, the second messengers linking mitochondrial dysfunction to initiation of mitophagy remain poorly characterized. Here, we show in mammalian and nematode neurons that Opa1 mutations trigger Ca2+-dependent mitophagy. Deletion or expression of mutated Opa1 in mouse retinal ganglion cells and Caenorhabditis elegans motor neurons lead to mitochondrial dysfunction, increased cytosolic Ca2+ levels, and decreased axonal mitochondrial density. Chelation of Ca2+ restores mitochondrial density in neuronal processes, neuronal function, and viability. Mechanistically, sustained Ca2+ levels activate calcineurin and AMPK, placed in the same genetic pathway regulating axonal mitochondrial density. Our data reveal that mitophagy in ADOA depends on Ca2+-calcineurin-AMPK signaling cascade.
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Project description:To elucidate molecular networks regulating important aspects of parasympathetic neuronal development, a genome-wide expression analysis was performed during multiple stages of avian ciliary ganglion (CG) development. The transcriptome data showed a well-defined sequence of events, starting from neuronal migration via neuronal fate cell determination, synaptic transmission, regulation of synaptic plasticity to growth factor associated signaling. Focusing on cell death-related changes in the transcriptome, we could characterize a series of events that starts with the activation of neuronal apoptotic processes at E7 via the cell death execution phase at E8 and E9 and ends with apoptotic cell clearance at E14. Moreover, we detected a transient up-regulation of the transcription factors TP53 and RARB that was linked to cell death. The expression of BID, a p53 target, was also found to be dynamically regulated. Using a virus-based RNAi knockdown approach, BID expression was shown to be crucial for the execution of ontogenetic programmed cell death (PCD). Therefore, this study for the first time provides a comprehensive analysis of CG neuron development on the transcriptome level, revealing a temporally well-controlled expression of genes regulating ontogenetic PCD, with BID being one of the most dynamically regulated genes during the cell death phase. The effect of BID silencing in vivo suggests an essential role of BID expression in neuronal development.
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