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 "neurodegeneration" symptom

adrenomyeloneuropathy

alexander disease

cadasil

canavan disease

classical phenylketonuria

fabry disease

gm1 gangliosidosis

hereditary cerebral hemorrhage with amyloidosis

krabbe disease

neonatal adrenoleukodystrophy

neuralgic amyotrophy

oculocutaneous albinism

pyruvate dehydrogenase deficiency

triple a syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

This symptom has already been validated