Defined neuronal populations drive fatal phenotype in a mouse model of Leigh syndrome

Bolea, Irène; Gella, Alejandro; Sanz, Elisenda; Prada-Dacasa, Patricia; Menardy, Fabien; Bard, Angela M; Machuca-Márquez, Pablo; Eraso-Pichot, Abel; Mòdol‐Caballero, Guillem; Navarro, Xavier; Kalume, Franck; Quintana, Albert

doi:10.7554/elife.47163

Cited by 40 publications

(72 citation statements)

References 70 publications

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“…Having demonstrated the high degree of specificity for Vglut2-driven Cre expression in RGCs histologically, we proceeded to establish a Vglut2-Cre;ndufs4 loxP/loxP transgenic mouse line in order to achieve RGC-specific deletion of ndufs4. The systemic phenotype of ndufs4 deletion in Vglut2-expressing glutamatergic neurons was recently described by another group which independently generated Vglut2-Cre;ndufs4 loxP/loxP transgenic mice but did not characterize the retinal phenotype 29 . Consistent with their report, we observed that Vglut2-Cre;ndufs4 loxP/loxP mice are initially healthy but develop progressive weight loss, ataxia, and hindlimb weakness beginning around P60.…”

Section: Rgc Somas and Axons Undergo Progressive Degeneration In Vglumentioning

confidence: 96%

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

Wang

Travis

Hao

et al. 2020

Sci Rep

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Optic atrophy resulting from retinal ganglion cell (RGC) degeneration is a prominent ocular manifestation of mitochondrial dysfunction. Although transgenic mice lacking the mitochondrial complex I accessory subunit NDUFS4 develop early-onset optic atrophy, severe systemic mitochondrial dysfunction leads to very early death and makes this mouse line impractical for studying the pathobiology of mitochondrial optic neuropathies. Theoretically, RGC-specific inactivation of ndufs4 would allow characterization of RGC degeneration over a longer time course, provided that RGC death from mitochondrial dysfunction is a cell-autonomous process. We demonstrate that the vesicular glutamate transporter VGLUT2 may be exploited to drive robust Cre recombinase expression in RGCs without any expression observed in directly neighboring retinal cell types. Deletion of ndufs4 in RGCs resulted in reduced expression of NDUFS4 protein within the optic nerves of Vglut2-Cre;ndufs4loxP/loxP mice. RGC degeneration in Vglut2-Cre;ndufs4loxP/loxP retinas commenced around postnatal day 45 (P45) and progressed to loss of two-thirds of RGCs by P90, confirming that intrinsic complex I dysfunction is sufficient to induce RGC death. The rapidly-developing optic atrophy makes the Vglut2-Cre;ndufs4loxP/loxP mouse line a promising preclinical model for testing therapies for currently untreatable mitochondrial optic neuropathies such as Leber Hereditary Optic Neuropathy.

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Section: Rgc Somas and Axons Undergo Progressive Degeneration In Vglumentioning

confidence: 96%

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

Wang

Travis

Hao

et al. 2020

Sci Rep

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“…Avoid installing the equipment in unstable surfaces or close to high-traffic areas.3. Close the chamber tightly and make sure the animal moves freely 4…”

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confidence: 99%

Measuring Breathing Patterns in Mice Using Whole-body Plethysmography

et al. 2020

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Respiratory dysfunction is among the main cause of severe and fatal pathologies worldwide. The use of effective experimental models and methodologies for the study of the pulmonary pathophysiology is necessary to prevent, control and cure these diseases. Plethysmography, a technique for the assessment of lung function, has been widely applied in mice for the characterization of respiratory physiology. However, classical plethysmography methods present technical limitations such as the use of anesthesia and animal immobilization. Whole-body plethysmography (WBP) avoids these issues providing a non-invasive approach for the assessment of the respiratory function in conscious animals. WBP relies on the recording of pressure changes that are produced by the spontaneous breathing activity of an animal placed inside an airtight chamber. During normal respiration, pressure variation is directly proportional to the respiratory pattern of the animal allowing the measurement of the respiratory rate and tidal volume. These parameters are commonly used to evaluate pulmonary function in different physiological and disease models. In contrast to classical plethysmography methods, WBP technique allows reproducible serial measurements as it avoids animal restraint or the use of anesthesia. These key features rend WBP a suitable approach for longitudinal studies allowing the assessment of progressive respiratory alterations in physiological and pathological conditions. This protocol describes the procedures for the measurement of the breathing patterns in mice using the WBP method, the data analysis and results interpretation.

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“…Glutamatergic neurons (Vglut2-expressing) in the VN have been proven susceptible to complex I 332 deficiency (Bolea et al, 2019). To define the factors driving this specific susceptibility, we first 333 confirmed the feasibility of the AAV-mitoTag approach for the isolation of mitochondria from this 334 genetically defined neuronal population in vivo.…”

Section: Cell Type-specific Isolation Of Mitochondria From Glutamatermentioning

confidence: 94%

“…NDUFS4 deficiency reveals a cell type-specific susceptibility to the disease. NDUFS4 ablation in 60 glutamatergic neurons (Vglut2-expressing) recapitulates most of the phenotype present in the global 61 NDUFS4-deficient mice (Bolea et al, 2019), thus warranting further study of glutamatergic neurons 62 in the VN. 63…”

Section: Introduction 38mentioning

confidence: 94%