Early oxidative damage underlying neurodegeneration in X-adrenoleukodystrophy

Abstract

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.

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

“…The second model was mice having a double gene knockout of both the Abcd1 and Abcd2 transporters (Abcd1 − /Abcd2 −/− ). The Abcd1 − /Abcd2 −/− mice, compared with the Abcd1 -mice, display greater VLCFA accumulation in the spinal cord, 19 higher levels of oxidative damage to proteins, 20 and a more severe AMN-like pathology with an earlier onset at 12 months of age. 19,67 It is worth mentioning that to date, no disease-causative role for ABCD2 has been found, although its absence provokes a partially overlapping fatty acid pattern when compared with the ABCD1-dependent biochemical phenotype.…”

“…The first model was Abcd1 -mice at 12 months of age. These mice already show biochemical signs of pathology, including oxidative stress 20 and alterations in energy homeostasis, 23 although the first clinical signs of AMN (that is, axonopathy and locomotor impairment) appear at 20 months. 18,19 We characterized the biochemical signs of adult X-ALD in these mice.…”

“…16,17,18 These animals present a late onset axonopathy in the spinal cord, in the absence of inflammatory demyelination in the brain, resembling the spastic paraparesis and lower extremity weakness of adrenomyeloneuropathy (AMN). 18,19 We previously reported oxidative damage in spinal cords from presymptomatic Abcd1 -mice, [20][21][22] together with metabolic failure, 23 disrupted mitochondrial biogenesis 24 and impaired mitochondrial oxidative phosphorylation and function. [25][26][27] Evidences for oxidative damage in X-ALD patients are also found in brain 28 and blood samples.…”

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…However, recently it was shown that, under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis itself actively induces neuronal death 32. Although the development of AMN occurs in the absence of overt inflammation, early oxidative damage including increased oxidative lesions and altered antioxidant defense is detected in the mouse spinal cord and human fibroblast cell lines 46. As the well‐known inducer of phosphatidylserine exposure, oxidative stress in AMN spinal cord may also prime for phagocytosis.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…More recently, oxidative stress has been proposed to contribute to the pathology. This is mainly based on the facts that (i) X-ALD plasma has increased levels of TBARS, carbonyls, and GSSG/GSH ratios (Vargas et al, 2004;Petrillo et al, 2013), (ii) X-ALD red blood cells display increased GPX activity (Vargas et al, 2004), and (iii) cultured X-ALD fibroblasts contain increased levels of modified lysine residues (and especially N1-carboxyethyl-lysine and N1-malondialdehyde-lysine) (Fourcade et al, 2008), elevated catalase and SOD activities (Vargas et al, 2004), and a higher sensitivity to L-buthionine-sulfoximine, an inhibitor of GSH synthesis (Fourcade et al, 2008). Similarly, two-fold more O…”