Photoreceptors in a mouse model of Leigh syndrome are capable of normal light-evoked signaling

Mitochondrial dysfunction is an important cause of heritable vision loss. Mutations affecting mitochondrial bioenergetics may lead to isolated vision loss or life-threatening systemic disease, depending on a mutations severity. Primary optic nerve atrophy resulting from death of retinal ganglion cells is the most prominent ocular manifestation of mitochondrial disease. However, dysfunction of other retinal cell types has also been described, sometimes leading to a loss of photoreceptors and retinal pigment epithelium that manifests clinically as pigmentary retinopathy. A popular mouse model of mitochondrial disease that lacks NADH:ubiquinone oxidoreductase subunit S4 (NDUFS4), a subunit of mitochondrial complex I, phenocopies many traits of the human disease Leigh syndrome, including the development of optic atrophy. It has also been reported that ndufs4-/- mice display diminished light responses at the level of photoreceptors or bipolar cells. By conducting electroretinography (ERG) recordings in live ndufs4-/- mice, we now demonstrate that this defect occurs at the level of retinal photoreceptors. We found that this deficit does not arise from retinal developmental anomalies, photoreceptor degeneration, or impaired regeneration of visual pigment. Strikingly, the impairment of ndufs4-/- photoreceptor function was not observed in ex vivo ERG recordings from isolated retinas, indicating that photoreceptors with complex I deficiency are intrinsically capable of normal signaling. The difference in electrophysiological phenotypes in vivo and ex vivo suggests that the energy deprivation associated with severe mitochondrial impairment in the outer retina renders ndufs4-/- photoreceptors unable to maintain the homeostatic conditions required to operate at their normal capacity

Assessing the Vitreopapillary Interface in Acute Nonarteritic Anterior Ischemic Optic Neuropathy

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute optic neuropathy in adults over age 50. While NAION typically occurs in patients with risk factors for microvascular ischemia, some have suggested an important mechanistic role for vitreous traction on the optic nerve head (ONH). Parsa and Hoyt have proposed that NAION is a misnomer and purely a tractional phenomenon. To test this hypothesis, we retrospectively assessed the posterior vitreous face by optical coherence tomography (OCT) in patients during the acute phase of NAION

Severe Leber Hereditary Optic Neuropathy Plus Disease in a Middle-Aged Man

A 50-year-old African American man with hypertension, atrial fibrillation, and congestive heart failure presented with progressive vision loss in both eyes over 3 months. He described blurriness and dimming of vision and changes in color perception. The patient also endorsed ascending numbness and paresthesias from his feet to hips bilaterally, with an onset 6 months before vision loss

Progressive Optic Atrophy in a Retinal Ganglion Cell-Specific Mouse Model of Complex I Deficiency (PDF)

Optic atrophy resulting from retinal ganglion cell (RGC) degeneration is the most prominent ocular manifestation of mitochondrial dysfunction. Efforts to develop effective pharmacotherapies for mitochondrial optic neuropathies have been hampered, in part, by the lack of an ideal preclinical animal model. Although mutant mice lacking the mitochondrial complex I accessory subunit NADH:ubiquinone oxidoreductase (NDUFS4) develop early-onset optic atrophy, severe systemic mitochondrial dysfunction leads to very early death, making this mouse line impractical for studying the pathobiology of mitochondrial optic neuropathy

Progressive Optic Atrophy in a Retinal Ganglion Cell-Specific Mouse Model of Complex I Deficiency (Video)

Optic atrophy resulting from retinal ganglion cell (RGC) degeneration is the most prominent ocular manifestation of mitochondrial dysfunction. Efforts to develop effective pharmacotherapies for mitochondrial optic neuropathies have been hampered, in part, by the lack of an ideal preclinical animal model. Although mutant mice lacking the mitochondrial complex I accessory subunit NADH:ubiquinone oxidoreductase (NDUFS4) develop early-onset optic atrophy, severe systemic mitochondrial dysfunction leads to very early death, making this mouse line impractical for studying the pathobiology of mitochondrial optic neuropathy

The V332A mutation abrogates peripherin’s outer segment targeting in rods of the <i>rds</i> mouse.

<p>(A) Wild type FLAG-tagged mouse peripherin (mPer) was electroporated into rods of the <i>rds</i> mouse and stained with anti-FLAG antibodies (green). (B) V332A FLAG-tagged peripherin electroporated into rods of the <i>rds</i> mouse; construct mislocalization to the inner segment and synaptic terminal is highlighted by white arrowheads. (C) V332A FLAG-tagged peripherin electroporated into the rods of wild type mice. The electroporated constructs are illustrated schematically above the corresponding panels with the position of the FLAG tag depicted in red. Note that the outer segment shapes in (A) and (C) are different due to ongoing photoreceptor degeneration in the <i>rds</i> mouse (A). Abbreviations are: OS – outer segment, IS – inner segment, N – nuclei, ST – synaptic termini. Nuclei (blue) are stained with Hoechst. Scale bar: 10 µm.</p

Mural Enhancement of the Intracranial Internal Carotid Artery in Giant Cell Arteritis

"While autopsy studies of patients with giant cell arteritis (GCA) have demonstrated inflammatory involvement of the internal carotid artery (ICA), radiologic signs of ICA inflammation have not been a prominent feature in the published literature. We present three patients with biopsy-proven GCA who demonstrated evidence of mural enhancement of the intracranial ICAs by magnetic resonance imaging (MRI).

The peripherin targeting signal is contained within a ten amino acid residue stretch.

<p>Panels show confocal images of transgenic frog retinas expressing the reporter construct YFP-xRhoCTΔ5 (green) fused to the fragments of the peripherin C-terminus illustrated in cartoons above the corresponding panels. Partial mislocalization of several constructs from rod outer segments is marked by white arrowheads. (A) The YFP-xRhoCTΔ5 reporter. (B) The reporter fused to xPer 317–336. (C) The reporter fused to xPer 317–327. (D) The reporter fused to xPer 327–336. (E–G) The reporter fused to xPer 317–336 sequences containing polyalanine amino acid substitutions indicated below the panels. Abbreviations are: OS – outer segment, IS – inner segment, N – nuclei, ST – synaptic termini. The nuclei (blue) are stained with Hoechst; scale bar: 5 µm. (H) A schematic of a frog rod photoreceptor illustrating its principle compartments.</p

Alanine scanning mutagenesis of the peripherin targeting sequence identifies V332 as the only residue essential for targeting.

<p>Panels A–I show confocal images of transgenic frog retinas expressing the YFP-xRhoCTΔ5-xPer317–336 (green) variations containing single alanine substitutions of individual residues. (J) Multiple sequence alignment of peripherin targeting sequences from different species; residues with over 90% identity are highlighted yellow and the 100% conserved valine is highlighted orange. Abbreviations are: OS – outer segment, IS – inner segment, N – nuclei, ST – synaptic termini. Nuclei (blue) are stained with Hoechst. Scale bar 5 µm.</p