RESUMEN
Purpose: To test whether continuous hypoxia is neuroprotective to retinal ganglion cells (RGCs) in a mouse model of mitochondrial optic neuropathy. Methods: RGC degeneration was assessed in genetically modified mice in which the floxed gene for the complex I subunit NDUFS4 is deleted from RGCs using Vlgut2-driven Cre recombinase. Beginning at postnatal day 25 (P25), Vglut2-Cre;ndufs4loxP/loxP mice and control littermates were housed under hypoxia (11% oxygen) or kept under normoxia (21% oxygen). Survival of RGC somas and axons was assessed at P60 and P90 via histological analysis of retinal flatmounts and optic nerve cross-sections, respectively. Retinal tissue was also assessed for gliosis and neuroinflammation using western blot and immunofluorescence. Results: Consistent with our previous characterization of this model, at least one-third of RGCs had degenerated by P60 in Vglut2-Cre;ndufs4loxP/loxP mice remaining under normoxia. However, continuous hypoxia resulted in complete rescue of RGC somas and axons at this time point, with normal axonal myelination observed on electron microscopy. Though only partial, hypoxia-mediated rescue of complex I-deficient RGC somas and axons remained significant at P90. Hypoxia prevented reactive gliosis at P60, but the retinal accumulation of Iba1+ mononuclear phagocytic cells was not substantially reduced. Conclusions: Continuous hypoxia achieved dramatic rescue of early RGC degeneration in mice with severe mitochondrial dysfunction. Although complete rescue was not durable to P90, our observations suggest that investigating the mechanisms underlying hypoxia-mediated neuroprotection of RGCs may identify useful therapeutic strategies for optic neuropathies resulting from less profound mitochondrial impairment, such as Leber hereditary optic neuropathy.
Asunto(s)
Enfermedades del Nervio Óptico , Células Ganglionares de la Retina , Ratones , Animales , Células Ganglionares de la Retina/patología , Gliosis/patología , Nervio Óptico/patología , Enfermedades del Nervio Óptico/prevención & control , Enfermedades del Nervio Óptico/patología , Axones/patología , Hipoxia/patología , Oxígeno , Modelos Animales de Enfermedad , Complejo I de Transporte de ElectrónRESUMEN
The type VI secretion system (T6SS) is widely distributed in diverse bacterial species and habitats where it is required for interbacterial competition and interactions with eukaryotic cells. Previous work described the role of a T6SS in the beneficial symbiont, Vibrio fischeri, during colonization of the light organ of Euprymna scolopes squid. However, the prevalence and diversity of T6SSs found within the distinct symbiotic structures of this model host have not yet been determined. Here, we analyzed 73 genomes of isolates from squid light organs and accessory nidamental glands (ANGs) and 178 reference genomes. We found that the majority of these bacterial symbionts encode diverse T6SSs from four distinct classes, and most share homology with T6SSs from more distantly related species, including pathogens of animals and humans. These findings indicate that T6SSs with shared evolutionary histories can be integrated into the cellular systems of host-associated bacteria with different effects on host health. Furthermore, we found that one T6SS in V. fischeri is located within a genomic island with high genomic plasticity. Five distinct genomic island genotypes were identified, suggesting this region encodes diverse functional potential that natural selection can act on. Finally, analysis of newly described T6SSs in roseobacter clade ANG isolates revealed a novel predicted protein that appears to be a fusion of the TssB-TssC sheath components. This work underscores the importance of studying T6SSs in diverse organisms and natural habitats to better understand how T6SSs promote the propagation of bacterial populations and impact host health.
RESUMEN
An 81-year-old woman developed painful vision loss to hand motions in the right eye over a several-day period. Dilated fundus examination revealed no acute pathology, but automated perimetry showed a superotemporal visual field defect in the asymptomatic left eye, suggestive of a junctional defect. Magnetic resonance imaging demonstrated enhancement of the right optic nerve extending to its junction with the optic chiasm. The patient's vision failed to improve with intravenous corticosteroids, but demonstrated significant improvement with therapeutic plasma exchange. She was subsequently found to be seropositive for aquaporin-4 autoantibodies, confirming the diagnosis of neuromyelitis optic spectrum disorder.