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.)
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, 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 Sep 3;34(36):12182-91.
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. J Neurosci, in revision.
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.
Lin W, Lin Y, Li J, Harding HP, Ron D, Jamison S. A deregulated integrated stress response promotes interferon-gamma-induced medulloblastoma. J Neurosci Res, 2011, 89(10):1586-1595.
Lin W, Popko B. Endoplasmic reticulum stress in disorders of myelinating cells. Nat Neurosci, 2009, 12(4):379-385.
Lin W, Kunkler PE, Harding HP, Ron D, Kraig RP, Popko B. Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon-gamma. Am J Pathol, 2008, 173(5):1508-1517.
Lin W, Bailey SL, Ho H, Harding HP, Ron D, Miller SD, Popko B. The integrated stress response prevents demyelination by protecting oligodendrocytes against immune-mediated damage. J Clin Invest, 2007, 117(2):448-456.
Lin W, Kemper A, Dupree JL, Harding HP, Ron D, Popko B. Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain, 2006, 129(Pt 5):1306-1318.
Lin W, Harding HP, Ron D, Popko B. Endoplasmic reticulum stress modulates the response of myelinating oligodendrocytes to the immune cytokine interferon-gamma. J Cell Biol, 2005, 169(4): 603-612.
Lin W, Kemper A, McCarthy K, Pytel P, Wang J, Campbell IL, Utset MF, Popko B. Interferon-gamma induced medulloblstoma in the developing cerebellum. J Neurosci, 2004, 24(45):10074-10083.