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Makhortova, Nina

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Makhortova

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Nina

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Makhortova, Nina
Author's Publications: search.filters.isAuthorOfPublication.2b53ec59-5a88-4e0a-a510-9962e2fe2eb6

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    Identification of a Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitor, BIP-135, That Prolongs the Median Survival Time of Δ7 SMA KO Mouse Model of Spinal Muscular Atrophy
    (American Chemical Society (ACS), 2013) Chen, Po C.; Gaisina, Irina N.; El-Khodor, Bassem F.; Ramboz, Sylvie; Makhortova, Nina; Rubin, Lee; Kozikowski, Alan P.
    The discovery of upregulated glycogen synthase kinase-3 (GSK-3) in various pathological conditions has led to the development of a host of chemically diverse small molecule GSK-3 inhibitors, such as BIP-135. GSK-3 inhibition emerged as an alternative therapeutic target for treating spinal muscular atrophy (SMA) when a number of GSK-3 inhibitors were shown to elevate survival motor neuron (SMN) levels in vitro and to rescue motor neurons when their intrinsic SMN level was diminished by SMN-specific short hairpin RNA (shRNA). Despite their cellular potency, the in vivo efficacy of GSK-3 inhibitors has yet to be evaluated in an animal model of SMA. Herein, we disclose that a potent and reasonably selective GSK-3 inhibitor, namely BIP-135, was tested in a transgenic Δ7 SMA KO mouse model of SMA and found to prolong the median survival of these animals. In addition, this compound was shown to elevate the SMN protein level in SMA patient-derived fibroblast cells as determined by Western blot, and was neuroprotective in a cell-based, SMA-related model of oxidative stress-induced neurodegeneration.
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    A screen for regulators of survival of motor neuron protein levels
    (Springer Nature, 2011) Makhortova, Nina; Hayhurst, Monica; Cerqueira, Antonio; Sinor-Anderson, Amy D; Zhao, Wen-Ning; Heiser, Patrick W; Arvanites, Anthony C.; Davidow, Lance; Waldon, Zachary O; Steen, Judith A; Lam, Kelvin; Ngo, Hien D; Rubin, Lee
    The motor neuron disease spinal muscular atrophy (SMA) results from mutations that lead to low levels of the ubiquitously expressed protein survival of motor neuron (SMN). An ever-increasing collection of data suggests that therapeutics that elevate SMN may be effective in treating SMA. We executed an image-based screen of annotated chemical libraries and discovered several classes of compounds that were able to increase cellular SMN. Among the most important was the RTK–PI3K–AKT–GSK-3 signaling cascade. Chemical inhibitors of glycogen synthase kinase 3 (GSK-3) and short hairpin RNAs (shRNAs) directed against this target elevated SMN levels primarily by stabilizing the protein. It was particularly notable that GSK-3 chemical inhibitors were also effective in motor neurons, not only in elevating SMN levels, but also in blocking the death that was produced when SMN was acutely reduced by an SMN-specific shRNA. Thus, we have established a screen capable of detecting drug-like compounds that correct the main phenotypic change underlying SMA.