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J Cell Biol. 2017 Nov 6;216(11):3655-3675. doi: 10.1083/jcb.201705085. Epub 2017 Sep 6.

A neuroprotective agent that inactivates prodegenerative TrkA and preserves mitochondria.

Author information

1
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada.
2
Department of Physiology, University of Toronto, Toronto, ON, Canada.
3
Department of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA.
4
Program in Cell Biology, Hospital for Sick Children, Toronto, ON, Canada.
5
Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
6
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada fredam@sickkids.ca.
7
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada dkaplan@sickkids.ca.

Abstract

Axon degeneration is an early event and pathological in neurodegenerative conditions and nerve injuries. To discover agents that suppress neuronal death and axonal degeneration, we performed drug screens on primary rodent neurons and identified the pan-kinase inhibitor foretinib, which potently rescued sympathetic, sensory, and motor wt and SOD1 mutant neurons from trophic factor withdrawal-induced degeneration. By using primary sympathetic neurons grown in mass cultures and Campenot chambers, we show that foretinib protected neurons by suppressing both known degenerative pathways and a new pathway involving unliganded TrkA and transcriptional regulation of the proapoptotic BH3 family members BimEL, Harakiri,and Puma, culminating in preservation of mitochondria in the degenerative setting. Foretinib delayed chemotherapy-induced and Wallerian axonal degeneration in culture by preventing axotomy-induced local energy deficit and preserving mitochondria, and peripheral Wallerian degeneration in vivo. These findings identify a new axon degeneration pathway and a potentially clinically useful therapeutic drug.

PMID:
28877995
PMCID:
PMC5674898
DOI:
10.1083/jcb.201705085
[Indexed for MEDLINE]
Free PMC Article

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