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Gino Cortopassi, Alfred K Yu, Lanying Song, Karl Murray; Leber's hereditary Optic Neuropathy: cellular pathophysiology, potential animal model, and cell-based drug screens for potential therapeutics. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3858.
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© ARVO (1962-2015); The Authors (2016-present)
Leber's hereditary Optic Neuropathy (LHON) is an inherited mitochondrial disease, resulting from mutations in mitochondrial complex 1, which cause degeneration of retinal ganglion cells, for which there is no cure. We analyzed pathomechanism in LHON cells, implicating the mitochondrial complex I defect, and ATF4 and CHOP and inflammatory markers. We show the ndufs4 complex 1 knockout mouse has significant depletion of RGC function, and RGC loss, coincident with a strong rise in multiple inflammatory markers. We have designed and improved cell-based screening assays of 6 mitochondrial functions in cybrids bearing the LHON mutation, and screened through 1600 FDA-approved drugs to identify those which rescue LHON-specific defects. The studies of pathomechanism support a model of LHON in which primary mutations drive complex I structural changes that cause an inflammatory response and RGC functional loss and death, and the drug screening studies identify potential therapeutics.
Microarrays were carried out as published previously. RNASeq and MicroElectrode Array (MEA) analysis of retinas of Ndufs4 KO and wild type controls were carried out using standard procedures.
Cell-based pathomechanism. Results include the mitochondrial complex-1 dependent induction of ATF4 and CHOP and potential inflammatory markers. LHON animal model. The ndufs4 KO mouse has loss of RGC function and RGC cell death as in human LHON, and a substantial induction of inflammatory markers in the retina, coincident with RGC functional loss by MEA. Drug based screening. Partial poisoning of complex I uncovers a LHON mutation-specific defect in complex I-driven ATP synthesis that can be screened for drugs that protect from this defect. Such drugs fall in particular structural and functional categories. Drug secondaries and mechanistic understanding. Secondary screening is in progress for hit confirmation, and mechanism of protective effect is being generated for particular hits. Testing in animal model of LHON. Top hits are entering animal testing, and preliminary results are likely to be available by the meeting time.
We have identified a mechanism of LHON, an animal model of LHON, and are screening therapeutics of potential benefit in LHON cells.
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