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HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage / Jin Young Kim; Siming Shen; Karen Dietz; Ye He; Owain Howell; Richard Reynolds; Patrizia Casaccia

Nature Neuroscience, Volume: 13, Issue: 2, Pages: 180 - 189

Swansea University Author: Howell, Owain

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DOI (Published version): 10.1038/nn.2471

Abstract

Histone deacetylase 1 (HDAC1) is a nuclear enzyme involved in transcriptional repression. We detected cytosolic HDAC1 in damaged axons in brains of humans with multiple sclerosis and of mice with cuprizone-induced demyelination, in ex vivo models of demyelination and in cultured neurons exposed to g...

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Published in: Nature Neuroscience
Published: 2010
Online Access: http://www.scopus.com/record/display.url?eid=2-s2.0-75549089982&origin=resultslist&sort=plf-f&src=s&st1=howell&st2=o.w&nlo=1&nlr=20&nls=&sid=942755C5CBB33656BBE96DCBEAC4A9AE.iqs8TDG0Wy6BURhzD3nFA%3a122&sot=anl&sdt=aut&sl=33&s=AU-ID%28%22Howell%2c+O.+W.%22+6602393502%29&relpos=12&relpos=12&searchTerm=AU-ID%28\%26quot%3BHowell%2C+O.+W.\%26quot%3B+6602393502%29
URI: https://cronfa.swan.ac.uk/Record/cronfa14216
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Abstract: Histone deacetylase 1 (HDAC1) is a nuclear enzyme involved in transcriptional repression. We detected cytosolic HDAC1 in damaged axons in brains of humans with multiple sclerosis and of mice with cuprizone-induced demyelination, in ex vivo models of demyelination and in cultured neurons exposed to glutamate and tumor necrosis factor-α. Nuclear export of HDAC1 was mediated by the interaction with the nuclear receptor CRM-1 and led to impaired mitochondrial transport. The formation of complexes between exported HDAC1 and members of the kinesin family of motor proteins hindered the interaction with cargo molecules, thereby inhibiting mitochondrial movement and inducing localized beading. This effect was prevented by inhibiting HDAC1 nuclear export with leptomycin B, treating neurons with pharmacological inhibitors of HDAC activity or silencing HDAC1 but not other HDAC isoforms. Together these data identify nuclear export of HDAC1 as a critical event for impaired mitochondrial transport in damaged neurons.
College: Swansea University Medical School
Issue: 2
Start Page: 180
End Page: 189