Functional overlap between ABCD1 (ALD) and ABCD2 (ALDR) transporters: a therapeutic target for X-adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disease caused by loss of function of the peroxisomal transporter ABCD1 (ALD), which results in accumulation of very long chain fatty acids (VLCFAs) in organs and serum, central demyelination and peripheral axonopathy and Addison's disease. Knockout of the ALD gene in the mouse (ALD(-)) results in an adrenomyeloneuropathy-like disease (a late onset form of X-ALD). In the present study, we demonstrate that axonal damage occurs as first pathological event in this model, followed by myelin degeneration. We show that this phenotype can be modulated through expression levels of an ALD-related gene (ALDR/ABCD2), its closest paralogue and a target of PPARalpha and SREBP transcription factors. Overexpression of ALDR in ALD(-) mice prevents both VLCFAs accumulation and the neurodegenerative features, whereas double mutants for ALD and ALDR exhibit an earlier onset and more severe disease (including signs of inflammatory reaction) when compared with ALD single mutants. Thus, our results provide direct evidence for functional redundancy/overlap between both transporters in vivo and highlight ALDR as therapeutic target for treatment of X-ALD.

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…Synapse loss has long been considered an integral aspect of neurodegeneration. Hence, we set out to examine the time course of axon degeneration and microglial activation in spinal cord 14. We found that as early as 8 months before synapse loss, spinal cord microglia of Abcd1 –/– mice display an enlarged soma and upregulated CD68 expression (Fig 1).…”

“…In AMN mice, previous studies have noted that microglial activation coincides with noninflammatory axonal degeneration13, 14; similar observations have been made in human AMN spinal cord 12. Despite these findings, no detailed studies on the molecular and functional change of microglia in the absence of ABCD1 have been conducted, and the impact of microglia upon long‐tract degeneration remains unclear.…”

Activation of sirtuin 1 as therapy for the peroxisomal disease adrenoleukodystrophy

“…We next examined the effects of SIRT1 activation in the axonopathy and associated locomotor disability exhibited in the X-ALD mouse model. 19 We used double mutants of Abcd1 and its closest homolog, the Abcd2 gene (Abcd1 − /Abcd2 −/− ), as they present with a more severe AMN-like phenotype with earlier axonal degeneration at approximately 12 months of age. This model has been successfully used to assay pharmacological and gene therapeutic strategies to combat AMN.…”

“…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. The second model was mice having a double gene knockout of both the Abcd1 and Abcd2 transporters (Abcd1 − /Abcd2 −/− ).…”

“…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.…”