HDAC1 upregulation in neurodegneration impairs neuronal mitochondrial transport
Kofi
which perhaps accounts for the gender bias in multiple sclerosis.
Testosterone is a carnitine transporter and given how the movement of
mitochondria is vital in neurotransmission, this might help link
testosterone and NGF signaling. In any case, it points to butyrate as
an important treatment option for M.S. and it also points to dietary
deficiency in fiber as a risk factor.
Nat Neurosci. 2009 Dec 27
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HDAC1 nuclear export induced by pathological conditions is essential for
the onset of axonal damage.
Kim JY, Shen S, Dietz K, He Y, Howell O, Reynolds R, Casaccia P.
[1] Graduate Program in Neuroscience at the Graduate School of
Biomedical Sciences, University of Medicine and Dentistry of New
Jersey-Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
[2] Department of Neuroscience and Genetics & Genomics, Mount Sinai
School of Medicine, New York, New York, USA.
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.
PMID: 20037577