Protein misfolding is linked to the development and pathology of many neurodegenerative diseases. The endoplasmic reticulum (ER) is a membrane-bound organelle essential for the folding of virtually all secreted and membrane proteins in eukaryotic cells. Pathologic events that interfere with ER protein folding cause ER stress. Cells activate the Unfolded Protein Response (UPR) when they are confronted with protein misfolding and ER stress. UPR signaling and chronic ER stress are seen in many neurodegenerative diseases. UPR signaling promotes cell death and pathology by mechanisms that are poorly understood. Studies from many labs have demonstrated that the UPR signal transduction pathway controlled by PRK-like ER Kinase (PERK) plays an important role in driving ER stress-induced cell death. PERK encodes an ER-resident transmembrane kinase with a luminal domain that detects misfolded proteins coupled to a cytosolic kinase domain and initiates a powerful translational and transcriptional program in response to ER stress. PERK activation leads to global translational attenuation. PERK activation concomitantly induces synthesis of transcription factors, including ATF4 and CHOP. Chronic PERK activation or forced over-expression of ATF4 and CHOP trigger cell death. Conversely, Chop-/- mice are partially resistant to ER stress-induced cell death. The mechanisms by which PERK, ATF4, and CHOP trigger apoptosis are poorly understood. We have recently discovered that chronic ER stress down-regulates the Inhibitor of Apoptosis (IAP) protein family through activity of the PERK-ATF4 signaling axis. Loss of IAPs sensitizes cells to ER stress-induced cell death. Based on these findings, we hypothesize that PERK-ATF4 regulation of IAPs determines whether cells succumb to apoptosis in response to chronic ER stress. To test this model and to further decipher the mechanisms by which PERK-ATF4 regulates XIAP and cell death, we propose the following Specific Aims: 1. Determine the mechanisms that regulate IAP proteins during ER stress. 2. Test the roles of IAP-domain family proteins in ER stress-induced neuronal cell death. 3. Determine the roles of PERK-induced miRNAs in regulating Iaps and cell survival in response to ER stress and protein misfolding. In summary, we propose experiments to decipher how PERK and ATF4 regulate the IAP protein family in response to protein misfolding and ER stress. The significance of our studies is that we will decipher molecular mechanisms that directly trigger apoptosis when cells are confronted with chronic ER stress and protein misfolding. These studies will positively impact society and patient care by identifying fundamental mechanisms governing the pathogenesis and progression of neuronal diseases arising from protein misfolding and ER stress, and these mechanisms can then be targeted to prevent cell death and thereby ameliorate disease.

Public Health Relevance

Protein misfolding leads to cell death and underlies the pathogenesis of many neurodegenerative disorders. The mechanisms that trigger apoptosis in response to protein misfolding are poorly understood. This project investigates the role of Unfolded Protein Response signaling in triggering neuronal cell death.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Gubitz, Amelie
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University of California, San Diego
Schools of Medicine
La Jolla
United States
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Yuan, Shauna H; Hiramatsu, Nobuhiko; Liu, Qing et al. (2018) Tauopathy-associated PERK alleles are functional hypomorphs that increase neuronal vulnerability to ER stress. Hum Mol Genet 27:3951-3963
Kroeger, Heike; Grimsey, Neil; Paxman, Ryan et al. (2018) The unfolded protein response regulator ATF6 promotes mesodermal differentiation. Sci Signal 11:
OrrĂ¹, Christina D; Soldau, Katrin; Cordano, Christian et al. (2018) Prion Seeds Distribute throughout the Eyes of Sporadic Creutzfeldt-Jakob Disease Patients. MBio 9:
Chiang, Wei-Chieh; Chan, Priscilla; Wissinger, Bernd et al. (2017) Achromatopsia mutations target sequential steps of ATF6 activation. Proc Natl Acad Sci U S A 114:400-405
Rodvold, Jeffrey J; Chiu, Kevin T; Hiramatsu, Nobuhiko et al. (2017) Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells. Sci Signal 10:
Chan, Priscilla; Stolz, Julia; Kohl, Susanne et al. (2016) Endoplasmic reticulum stress in human photoreceptor diseases. Brain Res 1648:538-541
Chiang, Wei-Chieh; Joseph, Victory; Yasumura, Douglas et al. (2016) Ablation of Chop Transiently Enhances Photoreceptor Survival but Does Not Prevent Retinal Degeneration in Transgenic Mice Expressing Human P23H Rhodopsin. Adv Exp Med Biol 854:185-91
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Kohl, Susanne; Zobor, Ditta; Chiang, Wei-Chieh et al. (2015) Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet 47:757-65

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