Stanford Advisors

All Publications

  • Neurodegeneration Risk Factor, EIF2AK3 (PERK), Influences Tau Protein Aggregation. The Journal of biological chemistry Park, G., Xu, K., Chea, L., Kim, K., Safarta, L., Song, K., Wu, J., Park, S., Min, H., Hiramatsu, N., Han, J., Lin, J. H. 2022: 102821


    Tauopathies are neurodegenerative diseases caused by pathologic misfolded tau protein aggregation in the nervous system. Population studies implicate EIF2AK3 (eukaryotic translation initiation factor 2 alpha kinase 3), better known as PERK (protein kinase R-like endoplasmic reticulum kinase), as a genetic risk factor in several tauopathies. PERK is a key regulator of intracellular proteostatic mechanisms - Unfolded Protein Response (UPR) and Integrated Stress Response (ISR). Previous studies found that tauopathy-associated PERK variants encoded functional hypomorphs with reduced signaling in vitro. But, it remained unclear how altered PERK activity led to tauopathy. Here, we chemically or genetically modulated PERK signaling in cell culture models of tau aggregation and found that PERK pathway activation prevented tau aggregation while inhibition exacerbated tau aggregation. In primary tauopathy patient brain tissues, we found that reduced PERK signaling correlated with increased tau neuropathology. We found that tauopathy-associated PERK variants targeted the ER luminal domain; and two of these variants damaged hydrogen bond formation. Our studies support that PERK activity protects against tau aggregation and pathology. This may explain why people carrying hypomorphic PERK variants have increased risk for developing tauopathies. Finally, our studies identify small molecule augmentation of PERK signaling as an attractive therapeutic strategy to treat tauopathies by preventing tau pathology.

    View details for DOI 10.1016/j.jbc.2022.102821

    View details for PubMedID 36563857

  • Reduction in endoplasmic reticulum stress activates beige adipocytes differentiation and alleviates high fat diet-induced metabolic phenotypes. Biochimica et biophysica acta. Molecular basis of disease Lee, J. M., Park, S., Lee, D., Ginting, R. P., Lee, M. R., Lee, M. W., Han, J. 2021; 1867 (5): 166099


    Endoplasmic reticulum (ER) stress is closely associated with various metabolic diseases, such as obesity and diabetes. Development of beige/brite adipocytes increases thermogenesis and helps to reduce obesity. Although the relationship between ER stress and white adipocytes has been studied considerably, the possible role of ER stress and the unfolded protein response (UPR) induction in beige adipocytes differentiation remain to be investigated. In this study we investigated how ER stress affected beige adipocytes differentiation both in vitro and in vivo. Phosphorylation of eIF2α was transiently decreased in the early phase (day 2), whereas it was induced at the late phase with concomitant induction of C/EBP homologous protein (CHOP) during beige adipocytes differentiation. Forced expression of CHOP inhibited the expression of beige adipocytes markers, including Ucp1, Cox8b, Cidea, Prdm16, and Pgc-1α, following the induction of beige adipocytes differentiation. When ER stress was reduced by the chemical chaperone tauroursodeoxycholic acid (TUDCA), the expression of the beige adipocytes marker uncoupling protein 1 (UCP1) was significantly enhanced in inguinal white adipose tissue (iWAT) and high fat diet (HFD)-induced abnormal metabolic phenotype was improved. In summary, we found that ER stress and the UPR induction were closely involved in beige adipogenesis. These results suggest that modulating ER stress could be a potential therapeutic intervention against metabolic dysfunctions via activation of iWAT browning.

    View details for DOI 10.1016/j.bbadis.2021.166099

    View details for PubMedID 33556486

  • ER Stress Induces Cell Cycle Arrest at the G2/M Phase Through eIF2α Phosphorylation and GADD45α. International journal of molecular sciences Lee, D., Hokinson, D., Park, S., Elvira, R., Kusuma, F., Lee, J. M., Yun, M., Lee, S. G., Han, J. 2019; 20 (24)


    Endoplasmic reticulum (ER) stress is known to influence various cellular functions, including cell cycle progression. Although it is well known how ER stress inhibits cell cycle progression at the G1 phase, the molecular mechanism underlying how ER stress induces G2/M cell cycle arrest remains largely unknown. In this study, we found that ER stress and subsequent induction of the UPR led to cell cycle arrest at the G2/M phase by reducing the amount of cyclin B1. Pharmacological inhibition of the IRE1α or ATF6α signaling did not affect ER stress-induced cell cycle arrest at the G2/M phase. However, when the alpha subunit of eukaryotic translation initiation factor 2 (eIF2α) phosphorylation was genetically abrogated, the cell cycle progressed without arresting at the G2/M phase after ER stress. GEO database analysis showed that growth arrest and DNA-damage-inducible protein α (Gadd45α) were induced in an eIF2a phosphorylation-dependent manner, which was confirmed in this study. Knockdown of GADD45α abrogated cell cycle arrest at the G2/M phase upon ER stress. Finally, the cell death caused by ER stress significantly reduced when GADD45α expression was knocked down. In conclusion, GADD45α is a key mediator of ER stress-induced growth arrest via regulation of the G2/M transition and cell death through the eIF2α signaling pathway.

    View details for DOI 10.3390/ijms20246309

    View details for PubMedID 31847234

    View details for PubMedCentralID PMC6940793

  • Modulation of Protein Synthesis by eIF2α Phosphorylation Protects Cell from Heat Stress-Mediated Apoptosis. Cells Park, S., Lim, Y., Lee, D., Elvira, R., Lee, J. M., Lee, M. R., Han, J. 2018; 7 (12)


    Global warming poses a considerable threat to human health, necessitating a proper understanding of mechanisms underlying cell death in the pathogenesis of heat-related diseases. Although mechanisms governing cytoplasmic response to heat are well understood, processes regulating cellular response to disruption of proteostasis in the endoplasmic reticulum (ER) due to heat stress remain unclear. The current study reveals that hyperthermic conditions may lead to a disturbance of ER homeostasis, also known as ER stress. Subsequent activation of the unfolded protein response (UPR) resulted in concomitant induction of cell death. Among the three UPR signaling pathways, the eIF2α phosphorylation pathway, and not the IRE1α/ATF6α pathways, is likely the main contributor to cell death under heat stress. Considering the role of eIF2α in translational control, we investigated the protective effect of translation rate on heat stress-mediated cell death. When protein synthesis was attenuated using cycloheximide or homoharringtonine, cell death due to heat stress was significantly reduced. In summation, we propose that transient modulation of protein synthesis by eIF2α phosphorylation has a pivotal role in protecting cells from heat stress-induced apoptosis. Therefore, pharmacological agents that promote eIF2α phosphorylation or reduce ER stress may contribute to the development of promising therapeutic approaches against heat-related diseases.

    View details for DOI 10.3390/cells7120254

    View details for PubMedID 30544621

    View details for PubMedCentralID PMC6316477