Adrenoleukodystrophy (ALD) is a rare neurometabolic disease caused by mutations in the ABCD1 gene, which encodes for the peroxisomal very long chain fatty acid (VLCFA) transporter. It is a debilitating disorder, which has a spectrum of clinical presentations. Since the accumulation of VLCFAs are a common feature of all ALD pathologies, we developed a substrate reduction therapy for ALD in the form of an inhibitor of Elovl1, the lipid elongase responsible for the generation of VLCFAs. This inhibitor was able to successfully reduce the accumulation of VLCFA in the brain and spinal cord of Abcd1 -/y mice. Single nuclei RNA-seq analysis demonstrated that altered lipid metabolism genes and pathways were corrected, however, there were also unexpected transcriptional changes unrelated to the loss of Abcd1, including an induction of the unfolded protein response. These data suggest that Elovl1 inhibition may have broader consequences in Abcd1 -/y mice beyond correction of lipid homeostasis.
Huang et al. (Thu,) studied this question.