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 ABCD1 gene, which encodes a peroxisomal transporter that plays a role in the import of VLCFA or VLCFA-
CoA into peroxisomes. The Abcd1 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 Abcd1 knockout mice as early as 3.5 months of age. At 12 months, Abcd1- 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 Abcd1- mice, and in human ALD fibroblasts, we also demonstrate that the loss of Abcd1 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.