Browsing by Subject "transgenic mice"

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    Motor neuron degeneration in spinal and Bulbar Muscular Atrophy is a skeletal muscle-driven process: Relevance to therapy development and implications for related motor neuron diseases.
    (Rare Dis, 2014) Cortes, Constanza J; La Spada, Albert R
    Non-cell autonomous degeneration has arisen as an important mechanism in neurodegenerative disorders. Using a novel line of BAC androgen receptor (AR) transgenic mice with a floxed transgene (BAC fxAR121), we uncovered a key role for skeletal muscle in X-linked Spinal and Bulbar Muscular Atrophy (SBMA), a motor neuronopathy caused by a polyglutamine expansion in exon 1 of the AR gene. By excising the mutant AR transgene from muscle only, we achieved complete rescue of neuromuscular phenotypes in these mice, despite retaining strong CNS expression. Furthermore, we delivered an antisense oligonucleotide (ASO) directed against the human AR transgene by peripheral injection, and documented that peripheral ASO delivery could rescue muscle weakness and premature death in BAC fxAR121 mice. Our results reveal a crucial role for skeletal muscle in SBMA disease pathogenesis, and offer an appealing avenue for therapy development for SBMA and perhaps also for related motor neuron diseases.
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    Photoreceptors in a Mouse Model of Leigh Syndrome are Capable of Normal Light-Evoked Signaling.
    (The Journal of biological chemistry, 2019-06-27) Gospe, Sidney M; Travis, Amanda M; Kolesnikov, Alexander V; Klingeborn, Mikael; Wang, Luyu; Kefalov, Vladimir J; Arshavsky, Vadim Y
    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 mutation's 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.