Abstract
The neurodegenerative disease X-linked adrenoleukodystrophy (X-ALD) is characterized by the abnormal accumulation of very long chain fatty acids. Mutations in the gene encoding the peroxisomal ATP-binding cassette half-transporter, adrenoleukodystrophy protein (ALDP), are the primary cause of X-ALD. To gain a better understanding of ALDP dysfunction, we searched for interaction partners of ALDP and identified binary interactions to proteins with functions in fatty acid synthesis (ACLY, FASN, and ACC) and activation (FATP4), constituting a thus far unknown fatty acid synthesis-transport machinery at the cytoplasmic side of the peroxisomal membrane. This machinery adds to the knowledge of the complex mechanisms of peroxisomal fatty acid metabolism at a molecular level and elucidates potential epigenetic mechanisms as regulatory processes in the pathogenesis and thus the clinical course of X-ALD.
Highlights
Dysfunction of the peroxisomal ATP-binding cassette (ABC) transporter adrenoleukodystrophy protein (ALDP) and elevated very long chain fatty acids are the hallmark of X-linked adrenoleukodystrophy (X-ALD)
We identified positive protein-protein interactions (PPI) of ALDP, PMP70, ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty-acid synthase (FASN), and Fatty acid transport protein 4 (FATP4) by use of GST pulldown experiments followed by mass spectrometry (LC/MS) and co-immunoprecipitation assays, as well as bioluminescence resonance energy transfer (BRET) measurements
Because loss of the biological function of ALDP alone is not sufficient to explain the onset of demyelination and the broad spectrum of disease severity in X-ALD, it is highly likely that a set of other proteins modulates the disease expression
Summary
Dysfunction of the peroxisomal ABC transporter ALDP and elevated very long chain fatty acids are the hallmark of X-ALD. To gain a better understanding of ALDP dysfunction, we searched for interaction partners of ALDP and identified binary interactions to proteins with functions in fatty acid synthesis (ACLY, FASN, and ACC) and activation (FATP4), constituting a far unknown fatty acid synthesis-transport machinery at the cytoplasmic side of the peroxisomal membrane. This machinery adds to the knowledge of the complex mechanisms of peroxisomal fatty acid metabolism at a molecular level and elucidates potential epigenetic mechanisms as regulatory processes in the pathogenesis and the clinical course of X-ALD. As these proteins are involved in sequential steps of lipid metabolism, our findings are in line with a novel, fatty acid synthesis-transport machinery located at the peroxisomal membrane
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