HDAC1 nuclear export induced by pathological conditions is essential for the onset of axonal damage

Nat Neurosci. 2010 Feb;13(2):180-9. doi: 10.1038/nn.2471. Epub 2009 Dec 27.

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-alpha. 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Animals
  • Axons / physiology*
  • Brain / physiopathology
  • Cell Nucleus / physiology*
  • Cells, Cultured
  • Cuprizone
  • Demyelinating Diseases / chemically induced
  • Demyelinating Diseases / physiopathology*
  • Glutamic Acid / metabolism
  • Histone Deacetylase 1 / metabolism*
  • Humans
  • Karyopherins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / physiology
  • Multiple Sclerosis / physiopathology
  • Neurons / physiology
  • Rats
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Time Factors
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear
  • Tumor Necrosis Factor-alpha
  • exportin 1 protein
  • Glutamic Acid
  • Cuprizone
  • HDAC1 protein, human
  • Hdac1 protein, mouse
  • Histone Deacetylase 1