Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy

Abstract

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD.

Methods: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis.

Results: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation.

Conclusions: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons.

Keywords: VLCFA; X-adrenoleukodystrophy; cerebral demyelination; neuroinflammation; oligodendrocytes; peroxisomes; spinal cord axonopathy.

Figure 1

Motor performance of Abcd1 KO mice (black squares) compared with wild type littermates (open circles) tested with rotarod (left) or bar walking score (right). The percentages of mice falling more quickly from the rotarod or having a low score on the bar is shown from 8 to 24 months of age [176].

Figure 2

Simplified scheme of the main mechanisms that appear to contribute to X-ALD phenotypes. (1) The primary event is VLCFA accumulation in OLs and other glial cells that leads to synthesis of VLCFA-rich myelin and toxic lipids, e.g., sphingosine-1-P (S1P). (2) Peroxisomal dysfunction affects OLs and other glial cells. (3) Axon dysfunction and variable degrees of axonal degeneration. (4) In cALD patients, demyelination, brain inflammation, and axon degeneration are triggered by the subacute activation of microglia, astrocytes, macrophages, then extensive infiltration of the brain white matter by immune cells.