Wensheng Lin, MD, Phd
Unfolded Protein Response in Neurological Diseases
The research in my laboratory is focused on understanding the effects of the unfolded protein response on neurological diseases and their underlying mechanisms.
Endoplasmic reticulum stress, initiated by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum lumen, activates an adaptive program known as the unfolded protein response, which coordinates endoplasmic reticulum protein-folding demand with protein-folding capacity and is essential to preserve cell function and survival under stressful conditions. Nevertheless, the unfolded protein response also controls an apoptotic program to eliminate cells whose folding problems in the endoplasmic reticulum cannot be resolved by the adaptive response. In eukaryotic cells, three endoplasmic reticulum–resident transmembrane proteins involved in the unfolded protein response have been identified: pancreatic ER kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). It has become increasingly clear that endoplasmic reticulum stress is an important feature of a number of neurological diseases, such as myelin disorders, neurodegenerative diseases, and brain tumors. Due to the double-edged sword nature of the unfolded protein response, the role that the unfolded protein response plays in these diseases remains ambiguous.
Our work utilizes sophisticated mouse models to dissect the precise role of individual branch of the unfolded protein response in myelin disorders, neurodegenerative diseases, and brain tumors. These studies could provide mechanistic insight necessary for designing novel therapeutic strategies for patients with these diseases.
Stone, S, Wu, S, Nave, K & Lin, W 2020, ‘The UPR preserves mature oligodendrocyte viability and function in adults by regulating autophagy of PLP’ JCI Insight. https://doi.org/10.1172/jci.insight.132364
Lin, W & Stone, S 2020, 'Unfolded protein response in myelin disorders', Neural Regeneration Research, vol. 15, no. 4, pp. 636-645. https://doi.org/10.4103/1673-5374.266903
Yue, Y, Stanojlovic, M, Lin, Y, Karsenty, G & Lin, W 2019, 'Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE' Journal of Neuroinflammation, vol. 16, no. 1, 23. https://doi.org/10.1186/s12974-019-1415-6
Chen, Y, Podojil, JR, Kunjamma, RB, Jones, J, Weiner, M, Lin, W, Miller, SD & Popko, B 2019, 'Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis' Brain, vol. 142, no. 2, pp. 344-361. https://doi.org/10.1093/brain/awy322
Yue, Y, Stone, S & Lin, W 2018, 'Role of nuclear factor ?b in multiple sclerosis and experimental autoimmune encephalomyelitis' Neural Regeneration Research, vol. 13, no. 9, pp. 1507-1515. https://doi.org/10.4103/1673-5374.237109
Stone, SM, Wu, S, Jamison, S, Durose, WW, Pallais, JP & Lin, W 2018, 'Activating transcription factor 6? deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases' GLIA, vol. 66, no. 7, pp. 1331-1345. https://doi.org/10.1002/glia.23307
Stone, SM, Jamison, S, Yue, Y, Durose, WW, Schmidt-Ullrich, R & Lin, W 2017, 'NF-?B activation protects oligodendrocytes against inflammation' Journal of Neuroscience, vol. 37, no. 38, pp. 9332-9344. https://doi.org/10.1523/JNEUROSCI.1608-17.2017
Lin, W 2017, 'Neuroprotective effects of vascular endothelial growth factor A in the experimental autoimmune encephalomyelitis model of multiple sclerosis' Neural Regeneration Research, vol. 12, no. 1, pp. 70-71. https://doi.org/10.4103/1673-5374.198982
Jiang, M, Liu, L, He, X, Wang, H, Lin, W, Wang, H, Yoon, SO, Wood, TL & Lu, QR 2016, 'Regulation of PERK-eIF2? signalling by tuberous sclerosis complex-1 controls homoeostasis and survival of myelinating oligodendrocytes' Nature Communications, vol. 7, 12185. https://doi.org/10.1038/ncomms12185
Ho, Y, Li, X, Jamison, S, Harding, HP, McKinnon, PJ, Ron, D & Lin, W 2016, 'PERK Activation Promotes Medulloblastoma Tumorigenesis by Attenuating Premalignant Granule Cell Precursor Apoptosis' American Journal of Pathology, vol. 186, no. 7, pp. 1939-1951. https://doi.org/10.1016/j.ajpath.2016.03.004