Etiology and treatment of adrenoleukodystrophy: new insights from Drosophila

Abstract

Adrenoleukodystrophy (ALD) is a fatal progressive neurodegenerative disorder affecting brain white matter. The most common form of ALD is X-linked (X-ALD) and results from mutation of the ABCD1-encoded very-long-chain fatty acid (VLCFA) transporter. X-ALD is clinically heterogeneous, with the cerebral form being the most severe. Diagnosed in boys usually between the ages of 4 and 8 years, cerebral X-ALD symptoms progress rapidly (in as little as 2 years) through declines in cognition, learning and behavior, to paralysis and ultimately to a vegetative state and death. Currently, there are no good treatments for X-ALD. Here, we exploit the Drosophila bubblegum (bgm) double bubble (dbb) model of neurometabolic disease to expand diagnostic power and therapeutic potential for ALD. We show that loss of the Drosophila long-/very-long-chain acyl-CoA synthetase genes bgm and/or dbb is indistinguishable from loss of the Drosophila ABC transporter gene ABCD. Shared loss-of-function phenotypes for synthetase and transporter mutants point to a lipid metabolic pathway association with ALD-like neurodegenerative disease in Drosophila; a pathway association that has yet to be established in humans. We also show that manipulation of environment increases the severity of neurodegeneration in bgm and dbb mutant flies, adding even further to a suite of new candidate ALD disease-causing genes and pathways in humans. Finally, we show that it is a lack of lipid metabolic pathway product and not (as commonly thought) an accumulation of pathway precursor that is causative of neurometabolic disease: addition of medium-chain fatty acids to the diet of bgm or dbb mutant flies prevents the onset of neurodegeneration. Taken together, our data provide new foundations both for diagnosing ALD and for designing effective, mechanism-based treatment protocols..

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

“…Disruption of dABCD in neurons results in retinal defects, which are not caused by the same alterations to glial cells. In the drosophilae model, environmental stress modifies penetrance and expressivity of neurodegeneration (Gordon et al, ). Interestingly, here the phenotype is rescued (reduction of retinal damage) with diet supplementation by medium‐chain‐FA; however, supplementation by long‐chain FA does not exacerbate disease.…”

“…species such as the drosophilae, mouse and zebra fish, the equivalent ABCD1 gene has been successfully targeted to generate knock-out models, each providing a unique strength and limitation (Forss-Petter et al, 1997;Gordon, Valdez, & Letsou, 2018;Kobayashi, Shinnoh, Kondo, & Yamada, 1997;Lu et al, 1997;Strachan et al, 2017).…”

“…Animal models provide a necessary platform in understanding the pathology of disease and serving as a test bed in demonstrating the biological significance of novel therapeutic interventions. In commonly used genetically malleable species such as the drosophilae, mouse and zebra fish, the equivalent ABCD1 gene has been successfully targeted to generate knock‐out models, each providing a unique strength and limitation (Forss‐Petter et al, ; Gordon, Valdez, & Letsou, ; Kobayashi, Shinnoh, Kondo, & Yamada, ; Lu et al, ; Strachan et al, ).…”

Rosy Beginnings: Studying Peroxisomes in Drosophila

“…Activated fatty acid molecules, such as very longchain acyl-CoA ester, are a substrate for the fatty acid transporter ATP-binding cassette sub-family D member 1 (ABCD1; Wiesinger et al, 2013). Knockdown of the potential Drosophila ABCD1/2 homolog showed optic lobe neurodegeneration very similar to that observed in the Bgm/Hll double knockout strain (reviewed in Gordon et al, 2018).…”

“…There are relatively few mutants of genes encoding fly homologs of peroxisome membrane proteins ( Table 2 ) and most UAS-RNAi lines or existing mutants are viable ( Thurmond et al, 2019 ). There are several mutants for ABCD which are viable and fertile, but targeted expression of UAS-RNAi targeting ABCD causes defects in the developing CNS and retina ( Gordon et al, 2018 ). Expression of UAS-RNAi constructs targeting Orct in the fat body in third instar larvae cause a lipid storage phenotype ( Fan et al, 2017 ).…”