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Neuroscience
 
Neuroscience Homepage  > Faculty List >Lin
Wensheng Lin, M.D., Ph.D.
Assistant Professor, Department of Neuroscience, Institute for Translational Neuroscience
linw@umn.edu

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.

Selected Publications
Lin W, Lin Y, Li J, Fenstermaker AG, Jamison S, Harding HP, Ron D, Popko B. Oligodendrocyte-specific activation of PERK signaling protects mice against experimental autoimmune encephalomyelitis. J Neurosci, in revision.
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.
  PATENTS
Brian Popko, Wensheng Lin. Animal models for demyelination disorders. U.S. Patent 7,423,194 and U.S. Patent 7,754,941.
Brian Popko, Wensheng Lin. Cell-based screen for agents useful for reducing neuronal demyelination or promoting neuronal remyelination. U.S. patent 7,884,260.
Brian Popko, Wensheng Lin. Methods for treating demyelination disorders. U.S. patent 8,053,627.
 
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