Progressive optic atrophy in a retinal ganglion cell-specific mouse model of complex I deficiency

Wang, Luyu; Travis, Amanda M.; Hao, Ying; Arshavsky, Vadim Y.; Gospe, Sidney M.

doi:10.1038/s41598-020-73353-0

Cited by 14 publications

(31 citation statements)

References 48 publications

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“…Glutamatergic neuron-specific Ndufs4 knockout mice (Vglut2:Ndufs4cKO mice) developed several of the symptoms observed in Ndufs4 −/− -WB mice, associated with a similar phenotype and leading to early death. 82 , 113 , 127 However, Vglut2:Ndufs4cKO mice did have a longer lifespan (∼10 weeks) 127 relative to Ndufs4 −/− -WB mice. 72 , 75 Although GABAergic neuron-specific loss of Ndufs4 (Gad2:Ndufs4cKO mice) resulted in failure to thrive, it was not associated with clinical symptoms compared to wild-type littermates.…”

Section: Results With Neuron-specific Ndufs4 Ko Mo...mentioning

confidence: 94%

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Wal

Adjobo‐Hermans

Keijer

et al. 2021

Brain

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Mitochondria are small cellular constituents that generate cellular energy (ATP) by oxidative phosphorylation (OXPHOS). Dysfunction of these organelles is linked to a heterogeneous group of multisystemic disorders, including diabetes, cancer, ageing-related pathologies and rare mitochondrial diseases (MDs). With respect to the latter, mutations in subunit-encoding genes and assembly factors of the first OXPHOS complex (CI) induce isolated CI deficiency and Leigh syndrome (LS). This syndrome is an early-onset, often fatal, encephalopathy with a variable clinical presentation and poor prognosis due to the lack of effective intervention strategies. Mutations in the nuclear DNA (nDNA)-encoded NDUFS4 gene, encoding the NADH: Ubiquinone oxidoreductase subunit S4 (NDUFS4) of CI induce “mitochondrial complex I deficiency, nuclear type 1” (MC1DN1) and LS in pediatric patients. A variety of (tissue-specific) Ndufs4 knockout mouse models were developed to study the LS pathomechanism and intervention testing. Here, we review and discuss the role of CI and NDUFS4 mutations in human MD, and review how the analysis of Ndufs4 knockout mouse models has generated new insights into the MC1ND1/LS pathomechanism and its therapeutic targeting.

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Section: Results With Neuron-specific Ndufs4 Ko Mo...mentioning

confidence: 94%

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Wal

Adjobo‐Hermans

Keijer

et al. 2021

Brain

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“…TeNT is a protease that cleaves the vesicular SNARE Synaptobrevin2/VAMP2 (Syb2), which is required for the exocytosis of neurotransmitters (Link et al, RGCs express Cre recombinase (Kerr et al, 2019;Sando et al, 2017;Zhang et al, 2008) and widespread expression of Cre occurs in the GCL of the retina as early as P0 (Figures 1D and S1A). Our selection of Calb2 Cre over Vglut2 Cre , another widely used transgenic line to target RGCs (Wang et al, 2020), was based on the relatively low expression of Calb2 mRNA in dLGN (Ahmadlou et al, 2018) as compared to Vglut2 (Land et al, 2004).…”

Section: Sonic Hedgehog (Shh) But Not Retinal Activity Is Critical Fo...mentioning

confidence: 99%

Sonic hedgehog-dependent recruitment of GABAergic interneurons into the developing visual thalamus

Somaiya

Stebbins

Xie

et al. 2022

Preprint

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SummaryAxons of retinal ganglion cells (RGCs) play critical roles in the development of inhibitory circuits in visual thalamus. We previously reported that RGC axons signal astrocytes to induce the expression of fibroblast growth factor 15 (FGF15), a motogen required for GABAergic interneuron migration into visual thalamus. However, how retinal axons induce thalamic astrocytes to generate Fgf15 and influence interneuron migration remains unknown. Here, we demonstrate that impairing RGC activity had no impact on interneuron recruitment into mouse visual thalamus. Instead, our data show that retinal-derived sonic hedgehog (SHH) is essential for interneuron recruitment. Specifically, we show that thalamus-projecting RGCs express SHH and thalamic astrocytes generate downstream components of SHH signaling. Deletion of RGC-derived SHH leads to a significant decrease in Fgf15 expression, as well as in the percentage of interneurons recruited into visual thalamus. Thus, our findings identify a morphogen-dependent neuron-astrocyte signaling mechanism essential for the migration of thalamic interneurons.

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“…The past decades have seen an increase in the use of genetically modified animal models in retinal research, which improved our knowledge of the cell-specific developmental, degenerative and rescue processes. They have been widely used in investigations of PR development ( Fong et al, 2005 ) and degeneration ( Geiger et al, 1994 ; Joseph and Li, 1996 ; Kanan et al, 2010 ; Tolmachova et al, 2010 ; Lipinski et al, 2011 ; Wu et al, 2012 ; Roman et al, 2018 ; Zhong et al, 2020 ); BC ( He et al, 2019 ; Yang et al, 2019 ), MC ( Peant et al, 2007 ) and GC degeneration ( Husain et al, 2014 ; Wang L. et al, 2020 ) and also in rescue processes ( McNally et al, 1999 ; Dong et al, 2007 ; Liu et al, 2012 ; Garcia-Caballero et al, 2018 ; Wang et al, 2019 ). However, the detailed discussion of genetic disorders leading to retinal degeneration are beyond the scope of the present review.…”

Section: Genetically Modified Experimental Models In the Study Of Retinal Healthmentioning

confidence: 99%

Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

et al. 2022

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The mammalian retina contains approximately 30 neuropeptides that are synthetized by different neuronal cell populations, glia, and the pigmented epithelium. The presence of these neuropeptides leaves a mark on normal retinal molecular processes and physiology, and they are also crucial in fighting various pathologies (e.g., diabetic retinopathy, ischemia, age-related pathologies, glaucoma) because of their protective abilities. Retinal pathologies of different origin (metabolic, genetic) are extensively investigated by genetically manipulated in vivo mouse models that help us gain a better understanding of the molecular background of these pathomechanisms. These models offer opportunities to manipulate gene expression in different cell types to help reveal their roles in the preservation of retinal health or identify malfunction during diseases. In order to assess the current status of transgenic technologies available, we have conducted a literature survey focused on retinal disorders of metabolic origin, zooming in on the role of retinal neuropeptides in diabetic retinopathy and ischemia. First, we identified those neuropeptides that are most relevant to retinal pathologies in humans and the two clinically most relevant models, mice and rats. Then we continued our analysis with metabolic disorders, examining neuropeptide-related pathways leading to systemic or cellular damage and rescue. Last but not least, we reviewed the available literature on genetically modified mouse strains to understand how the manipulation of a single element of any given pathway (e.g., signal molecules, receptors, intracellular signaling pathways) could lead either to the worsening of disease conditions or, more frequently, to substantial improvements in retinal health. Most attention was given to studies which reported successful intervention against specific disorders. For these experiments, a detailed evaluation will be given and the possible role of converging intracellular pathways will be discussed. Using these converging intracellular pathways, curative effects of peptides could potentially be utilized in fighting metabolic retinal disorders.

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Progressive optic atrophy in a retinal ganglion cell-specific mouse model of complex I deficiency

Cited by 14 publications

References 48 publications

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention

Sonic hedgehog-dependent recruitment of GABAergic interneurons into the developing visual thalamus

Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice

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