@article{a91414b9681e44f9962559df7d7c7fa9,
title = "Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination",
abstract = "Axonal damage has been associated with aberrant protein trafficking. We examined a newly characterized class of compounds that target nucleo-cytoplasmic shuttling by binding to the catalytic groove of the nuclear export protein XPO1 (also known as CRM1, chromosome region maintenance protein 1). Oral administration of reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but was also observed in another mouse model of axonal damage (that is, kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection.",
author = "Haines, {Jeffery D.} and Olivier Herbin and {De La Hera}, Bel{\'e}n and Vidaurre, {Oscar G.} and Moy, {Gregory A.} and Qingxiang Sun and Fung, {Ho Yee Joyce} and Stefanie Albrecht and Konstantina Alexandropoulos and Dilara McCauley and Chook, {Yuh Min} and Tanja Kuhlmann and Kidd, {Grahame J.} and Sharon Shacham and Patrizia Casaccia",
note = "Funding Information: We thank T. Flagiello and X. Pedre for assistance with EAE animal experiments. The project was supported by US National Institutes of Health grants R01-NS69385 and R37-NS42925, seed funds from Karyopharm Therapeutics to P.C., and the Fast Forward division of the National Multiple Sclerosis Society to P.C. and S.S. T.K. was supported by funds from the Interdisciplinary Centre for Clinical Research in M{\"u}nster (KuT3/006/11). O.H. is the recipient of the Mount Sinai Helmsley Award. J.D.H. holds a postdoctoral fellowship from the Multiple Sclerosis Society of Canada and the Fonds de la recherche en sant{\'e} du Qu{\'e}bec. Human tissue samples for western blotting were supplied by the UK Multiple Sclerosis Tissue Bank, funded by the MS Society of Great Britain and Northern Ireland, registered charity 207495. Publisher Copyright: {\textcopyright} 2015 Nature America, Inc. All rights reserved.",
year = "2015",
month = apr,
day = "28",
doi = "10.1038/nn.3953",
language = "English (US)",
volume = "18",
pages = "511--520",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "4",
}