Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy.

[adrenomyeloneuropathy]

X-linked adrenoleukodystrophy (X-ALD ) is a fatal neurodegenerative disorder , characterized by progressive cerebral demyelination cerebral childhood adrenoleukodystrophy (CCALD ) or spinal cord neurodegeneration (adrenomyeloneuropathy , AMN ), adrenal insufficiency and accumulation of very long -chain fatty acids (VLCFA ) in tissues . The disease is caused by mutations in the ABCD 1 gene , which encodes a peroxisomal transporter that plays a role in the import of VLCFA or VLCFA-CoA into peroxisomes . The Abcd 1 knockout mice develop a spinal cord disease that mimics AMN in adult patients , with late onset at 20 months of age . The mechanisms underlying cerebral demyelination or axonal degeneration in spinal cord are unknown . Here , we present evidence by gas chromatography /mass spectrometry that malonaldehyde-lysine , a consequence of lipoxidative damage to proteins , accumulates in the spinal cord of Abcd 1 knockout mice as early as 3 .5 months of age . At 12 months , Abcd 1 - mice accumulate additional proteins modified by oxidative damage arising from metal-catalyzed oxidation and glycoxidation /lipoxidation . While we show that VLCFA excess activates enzymatic antioxidant defenses at the protein expression levels , both in neural tissue , in ex vivo organotypic spinal cord slices from Abcd 1 - mice , and in human ALD fibroblasts , we also demonstrate that the loss of Abcd 1 gene function hampers oxidative stress homeostasis . We find that the alpha-tocopherol analog Trolox is able to reverse oxidative lesions in vitro , thus providing therapeutic hope . These results pave the way for the identification of therapeutic targets that could reverse the deregulated response to oxidative stress in X-ALD .

Diseases
Validation

Diseases presenting "cerebral demyelination" symptom

adrenomyeloneuropathy

neonatal adrenoleukodystrophy

x-linked adrenoleukodystrophy

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