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.
(For a comprehensive list of recent publications, refer to PubMed, a service provided by the National Library of Medicine.)
- Wu S, Stone S, Nave KA, Lin W. The integrated UPR and ERAD in oligodendrocytes maintains myelin thickness in adults by regulating myelin protein translation. J Neurosci. 2020 Sep 21:JN-RM-0604-20.
- Wu S, Stone S, Yue Y, Lin W. Endoplasmic reticulum associated degradation is required for maintaining endoplasmic reticulum homeostasis and viability of mature Schwann cells in adults. Glia. 2020 Sep 16. doi: 10.1002/glia.23910.
- Lin W, Stone S. Unfolded protein response in myelin disorders. Neural Regen Res. 2020;15(4):636-645.
- Yue Y, Stanojlovic M, Lin Y, Karsenty G, Lin W. Oligodendrocyte-specific ATF4 inactivation does not influence the development of EAE. J Neuroinflammation. 2019 Feb 1;16(1):23.
- Stone S, Yue Y, Stanojlovic M, Wu S, Karsenty G, Lin W. Neuron-specific PERK inactivation exacerbates neurodegeneration during experimental autoimmune encephalomyelitis. JCI Insight. 2019 Jan 24;4(2). pii: 124232.
- Yue Y, Stone S, Lin W. Role of nuclear factor κB in multiple sclerosis and experimental autoimmune encephalomyelitis. Neural Regen Res. 2018 Sep;13(9):1507-1515.
- Stone S, Wu S, Jamison S, Durose W, Pallais JP, Lin W. Activating transcription factor 6α deficiency exacerbates oligodendrocyte death and myelin damage in immune-mediated demyelinating diseases. Glia. 2018;66(7):1331-1345.
- Stone S, Jamison S, Yue Y, Durose W, Schmidt-Ullrich R, Lin W. NF-κB activation protects oligodendrocytes against inflammation. J Neurosci. 2017;37:9332-9344.
- Lin W. Neuroprotective effects of vascular endothelial growth factor A in the experimental autoimmune encephalomyelitis model of multiple sclerosis. Neural Regen Res. 2017;12(1):70-71.
- Stone S, Ho Y, Li X, Jamison S, Harding HP, Ron D, Lin W. Dual role of the integrated stress response in medulloblastoma tumorigenesis. Oncotarget. 2016;7(39):64124-64135.
- Stanojlovic M, Pang X, Lin Y, Stone S, Cvetanovic M, Lin W. Inhibition of vascular endothelial growth factor receptor 2 exacerbates loss of lower motor neurons and axons during experimental autoimmune encephalomyelitis. PLoS One. 2016 Jul 28;11(7):e0160158.
- Stone S, Lin W. The unfolded protein response in multiple sclerosis. Front Neurosci, 2015, 9:264.
- Jamison S, Lin Y, Lin W. Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A. PLoS ONE; 2015;10(3): e0120252.
- Lin W. Impaired eIF2B activity in oligodendrocytes contributes to VWMD pathogenesis. Neural Regen Res, 2015;10(2):195-197.
- Lin Y, Pang X, Huang G, Jamison S, Fang J, Harding HP, Ron D, Lin W. Impaired eukaryotic translation initiation factor 2B activity specifically in oligodendrocytes reproduces the pathology of vanishing white matter disease in mice. J Neurosci. 2014;34(36):12182-12191.
- Lin Y, Huang G, Jamison S, Li J, Harding HP, Ron D, Lin W. PERK activation preserves the viability and function of remyelinating oligodendrocytes in immune-mediated demyelinating diseases. Am J Pathol. 2014;184(2):507-19.
- Lin W, Lin Y, Li J, Fenstermaker AG, Way WS, Clayton B, Jamison S, Harding HP, Ron D, Popko B. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis. J Neurosci. 2013,33(14):5980-5991.
- Lin Y, Jamison S, Lin W. Interferon-gamma activates nuclear factor-κB in oligodendrocytes through a process mediated by the unfolded protein response. PLoS ONE. 2012,7(5): e36408.