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Updated: Apr 17, 2026
Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination
Jeffery D Haines1, Olivier Herbin2, Belén de la Hera1
1Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
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.
Insights
New compounds targeting nuclear export protein XPO1 (CRM1) show promise in protecting against axonal damage and demyelination. These CRM1 inhibitors reduced disease progression and preserved neuronal integrity in preclinical models.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Aberrant protein trafficking is linked to axonal damage.
- Nuclear export protein XPO1 (CRM1) regulates nucleo-cytoplasmic shuttling.
Purpose of the Study:
- To investigate the neuroprotective potential of novel CRM1 inhibitors.
- To assess the efficacy of CRM1 inhibition in models of axonal damage and demyelination.
Main Methods:
- Administration of reversible CRM1 inhibitors in murine models of demyelination and kainic acid-induced axonal damage.
- Assessment of disease progression, immune cell proliferation, cytoskeletal integrity, and protein localization.
- Proteomic analysis to identify CRM1 target molecules in neurons.
Main Results:
- CRM1 inhibitors significantly attenuated disease progression in preclinical models, even when treatment started after paralysis onset.
- Inhibitors decreased immune cell proliferation and preserved cytoskeletal integrity in demyelinated axons.
- Neuroprotection was observed across different models of axonal damage, including cultured neurons with XPO1 knockdown.
Conclusions:
- Targeting CRM1-mediated nucleo-cytoplasmic shuttling offers a potential therapeutic strategy for neurodegenerative diseases.
- CRM1 inhibitors prevent the nuclear export of detrimental proteins and retain neuroprotective transcription factors in neurons.
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