Understanding X-ALD: Easy as ABC (ATP-Binding Cassettes)

Adrenoleukodystrophy (X-ALD) is an X-linked disorder that causes severe neurodegeneration. The hallmark of X-ALD is an accumulation of very long chain fatty acids (VLCFA) in tissues.  VLCFA are taken into peroxisomes to be degraded by a transport protein found on the membrane of peroxisomes.  While mutations in this transport protein, ABCD1, have long been linked to the accumulation of VLCFA, there have been some discrepancies.  VLCFA must be turned into to their acyl-CoA form by an enzyme called ACSVL to be broken down.  Some researchers have observed that the acyl-CoA form is still degraded in X-ALD fibroblasts, which suggests that VLCFA accumulate because ACSVL is not working.  This casts doubt on the important role of ABCD1 in causing X-ALD.  Wiesinger et al. (2013) finally put an end to this debate by definitively establishing that ABCD1 mutations cause X-ALD.

The authors used fibroblasts, which are cells that make connective tissue, taken from X-ALD patients for their studies because this is the most common way for scientists to study X-ALD.  When they added VLCFA-CoA to these cells, it was not degraded just like the free fatty acid forms.  To further demonstrate the role of ABCD1, VLCFA-CoA was added to normal fibroblasts where ABCD1 was being blocked by an antibody.  This mimicked the pathology of X-ALD and the levels of VLCFA-CoA remained high, just like in the X-ALD fibroblasts.  These experiments determined that the CoA forms of VLCFA are a substrate for ABCD1, and therefore, the defect in X-ALD that leads to VLCFA accumulation comes from ABCD1 mutations, not a defect in the enzyme that makes the acyl-CoA esters of VLCFA.

Now that the authors determined ABCD1 was causing the problems, they investigated how this could be solved.  Since there is still some residual β-oxidation of VLCFA, some researchers have proposed that another transporter protein, either ABCD2 or ABCD3, could be stimulated so as to make up for the loss of ABCD1.  By measuring mRNA expression with quantitative PCR and protein levels using a Western Blot, the authors determined that ABCD2 is not expressed at a high enough quantity to have a real affect on VLCFA, but ABCD3 is highly expressed.  With this information, they blocked ABCD3 with an antibody and found that the residual β-oxidation of VLCFA was cut in half.  This means that it must be responsible for the remaining degradation of these fatty acids.  The authors, therefore, settled the debate about the biochemical source for VLCFA accumulation and offer a therapeutic approach for treating X-ALD.