Evolution of adrenoleukodystrophy model systems

Abstract

X‐linked adrenoleukodystrophy (ALD) is a neurometabolic disorder affecting the adrenal glands, testes, spinal cord and brain. The disease is caused by mutations in the ABCD1 gene resulting in a defect in peroxisomal degradation of very long‐chain fatty acids and their accumulation in plasma and tissues. Males with ALD have a near 100% life‐time risk to develop myelopathy. The life‐time prevalence to develop progressive cerebral white matter lesions (known as cerebral ALD) is about 60%. Adrenal insufficiency occurs in about 80% of male patients. In adulthood, 80% of women with ALD also develop myelopathy, but adrenal insufficiency or cerebral ALD are very rare. The complex clinical presentation and the absence of a genotype‐phenotype correlation are complicating our understanding of the disease. In an attempt to understand the pathophysiology of ALD various model systems have been developed. While these model systems share the basic genetics and biochemistry of ALD they fail to fully recapitulate the complex neurodegenerative etiology of ALD. Each model system recapitulates certain aspects of the disorder. This exposes the complexity of ALD and therefore the challenge to create a comprehensive model system to fully understand ALD. In this review, we provide an overview of the different ALD modeling strategies from single‐celled to multicellular organisms and from in vitro to in vivo approaches, and introduce how emerging iPSC‐derived technologies could improve the understanding of this highly complex disorder.

The physiological functions of human peroxisomes

“…The study of the Abcd1 -/mouse models did not shed further light on the pathological mechanisms in the adrenal cortex (443). VLCFA accumulated in the adrenals, which was amplified in double Abcd1/Abcd2 -/mice, but this did not result in adrenal insufficiency.…”

Mouse Models to Study Peroxisomal Functions and Disorders: Overview, Caveats, and Recommendations

“…The three ABCD transporters that bind ATP and import (likely) fatty acyl-CoAs, to be metabolized in various pathways, and C27-bile acid CoAs, to be chain shortened by β-oxidation, were inactivated by classical gene targeting [100][101][102][103][104]. ABCD1 knockouts mimic the common myeloneuropathy phenotype of X-linked adrenoleukodystrophy (ALD) patients but do not develop cerebral leukodystrophy nor adrenal atrophy or dysfunction [105,106]. By generating double ABCD1 -PEX7 knockouts, synergism between VLCFA accumulation and plasmalogen depletion with regard to pathological consequences was shown.…”

“…The adrenomyeloneuropathy (AMN) phenotype was precipitated by generating mice deficient in both ABCD1 and ABCD2, that have overlapping substrate specificities [103]. With the purpose to elicit a leukodystrophy phenotype, ABCD1 knockouts were challenged in several ways and crossed with other gene manipulated mouse models, however without success (reviewed in [105]). ABCD3 knockouts only developed liver enlargement accompanied by an increased ratio of C27/C24 bile acids [104] and branched chain fatty acid accumulations after supplementing them with phytol.…”

The Role of Oxidative Stress and Inflammation in X-Link Adrenoleukodystrophy

“…In addition, various animal models with both advantages and drawbacks were used to study the mechanism of X-ALD (74,75). ABCD1 knockout mice that exhibit delayed (20 months) onset axonopathy in the spinal cord without cerebral inflammatory demyelination (76), which are considered to mimic AMN, are often used to evaluate changes in biochemical markers.…”