Apoptosis is a type of programmed cell death that regulates cellular physiology. Apoptosis can be activated by cell stresses, such as unfolded proteins. We have discovered a novel protein mediating mitochondrial outer membrane permeabilization in response to unfolded protein expression, using a small molecule screening approach. We screened 47,000 small molecules for those that could prevent polyglutamine- induced apoptosis in PC12 cells and identified three effective compounds. Using an affinity purification approach, we found that all four compounds act by inhibiting the same target. We found that upon expression of polyglutamine in PC12 cells, this target protein accumulates in mitochondria and activates the intrinsic apoptotic pathway by inducing mitochondrial outer membrane permeabilization (MOMP). We propose to define the mechanism by which these compounds inhibit the pro-apoptotic activity of this protein, and to determine how this protein induces MOMP, including identifying binding partners for this protein in the mitochondrial outer membrane. These studies may define a new apoptotic pathway.
Our goal is to define a new mechanism for inducing apoptosis in neurons. This mechanism may be involved in neurodegeneration. Small molecule inhibitors of this mechanism may eventually provide new therapeutic agents for neurodegenerative diseases.
|Viswanathan, Vasanthi S; Ryan, Matthew J; Dhruv, Harshil D et al. (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547:453-457|
|Welsch, Matthew E; Kaplan, Anna; Chambers, Jennifer M et al. (2017) Multivalent Small-Molecule Pan-RAS Inhibitors. Cell 168:878-889.e29|
|Shimada, Kenichi; Hayano, Miki; Pagano, Nen C et al. (2016) Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as Biomarker for Ferroptosis Sensitivity. Cell Chem Biol 23:225-235|
|Yang, Wan Seok; Kim, Katherine J; Gaschler, Michael M et al. (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A 113:E4966-75|
|Hayano, M; Yang, W S; Corn, C K et al. (2016) Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 23:270-8|
|Shimada, Kenichi; Skouta, Rachid; Kaplan, Anna et al. (2016) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 12:497-503|
|Yang, Wan Seok; Stockwell, Brent R (2016) Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol 26:165-176|
|Larraufie, Marie-Helene; Yang, Wan Seok; Jiang, Elise et al. (2015) Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility. Bioorg Med Chem Lett 25:4787-92|
|Kaplan, Anna; Gaschler, Michael M; Dunn, Denise E et al. (2015) Small molecule-induced oxidation of protein disulfide isomerase is neuroprotective. Proc Natl Acad Sci U S A 112:E2245-52|
|Dixon, Scott J; Winter, Georg E; Musavi, Leila S et al. (2015) Human Haploid Cell Genetics Reveals Roles for Lipid Metabolism Genes in Nonapoptotic Cell Death. ACS Chem Biol 10:1604-9|
Showing the most recent 10 out of 33 publications