| NDUFS4: Creation of the First Complex I Mouse Model Mimicking Leigh Syndrome | |
Abstract/OtherAbstract
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Carl A Pinkert and Shey-Shing Sheu, Faculty Advisors. Thesis - (PhD) - Genetics, Genomics and Development, School of Medicine and Dentistry, University of Rochester., Leigh syndrome is an inherited neurometabolic disorder primarily affecting muscle tissue and the nervous system. Disease manifestations are often observed in infants and can be caused by a number of separate mutations involved in energy production and more specifically in the mitochondrial electron transport chain. Mutations in mitochondrial proteins can lead to Leigh syndrome via either pyruvate dehydrogenase deficiency or a bottleneck in the electron transport chain function. The proteins affected by this energetic deficiency have been shown to be involved in support of the electron transport chain or in Complexes I-V directly. Various mutations in the NADH dehydrogenase-ubiquinone-FeS 4 (NDUFS4) gene have been associated with decreased Complex I activity in mitochondrial electron transport and Leigh syndrome. A mouse model harboring a point mutation in the NDUFS4 gene was created to effectively truncate the encoded protein product. The underlying hypothesis was that this truncation would cause decreased Complex I activity which would in turn lead to a Leigh disease phenotype. In initial matings, homozygosity of the point mutation appeared lethal. Therefore, mice heterozygous for the point mutation were characterized. Mitochondria obtained from heterozygotes demonstrated a decreased respiration rate following use of glutamate and malate as substrates with no effect following succinate as a substrate; representing hallmarks of a Complex I disorder. Further, a decreased Complex I activity with steady-state Complex II activity, combined with an increased lactate accumulation, were consistent with Leigh syndrome phenotype. Accordingly, this model will allow for characterization of current and future therapeutic treatments; from dietary mediation to proposed gene therapies. By dissecting the various manifestations of disease at the whole animal, tissue, and cellular levels, coupled with examination of putative alternative endogenous pathways – insights into Leigh syndrome disease progression can now be addressed., NIH (ND053037 and RR16286) |
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Contributors
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Ingraham, Christopher |
Publication Detail
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Publisher : - Type : Thesis Format : 3116782 bytes, application/pdf |
Date Detail
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2008-08-01, 2008-08-01, 2008-08-01 |
Subject
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NDUFS4, Leigh Syndrome, Complex I, Mitochondrial Disease, Neurodegenerative Disease |
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Other Details
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Languages : en |
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