Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination
| Autor: | Dilara McCauley, Patrizia Casaccia, Stephanie Albrecht, Belén de la Hera, Sharon Shacham, Oscar G. Vidaurre, Yuh Min Chook, Grahame J. Kidd, Tanja Kuhlmann, Konstantina Alexandropoulos, Olivier Herbin, Jeffery D. Haines, Ho Yee Joyce Fung, Gregory Moy, Qingxiang Sun |
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| Rok vydání: | 2015 |
| Předmět: |
0303 health sciences
Gene knockdown General Neuroscience Biology Cell cycle Neuroprotection 03 medical and health sciences Cell nucleus XPO1 0302 clinical medicine Neuroimmunology medicine.anatomical_structure medicine Nuclear export signal Neuroscience Transcription factor 030217 neurology & neurosurgery 030304 developmental biology |
| Zdroj: | Nature Neuroscience. 18:511-520 |
| ISSN: | 1546-1726 1097-6256 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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