Dissection of neurometabolic disease using drosophilia melanogaster: bubblegum and double bubble mutants suggest new cellular defects in adrenoleukodystrophy pathology

Altered lipid metabolism is a recognized contributor to neurodegenerative (ND) conditions, both rare and common, such as Adrenoleukodystrophy (ALD) and Alzheimer's disease that affect millions of individuals worldwide. For most of these diseases, therapeutic options are limited. Significant therapeutic progress might be expected with the development of animal models. Two Drosophila mutants fail to activate long- and very long-chain FAs (acyl CoA-synthetases, ACS) were used to probe the relationship between lipid homeostasis and nervous system function with the overarching goal of determining the primary cell type affected, and the specific subcellular defect in an animal model for ALD (Figure 1.1 A, B). Adults homozygous for mutations in bubblegum (bgm) or double bubble (dbb) exhibit increased very long chain FA levels, a distinguishing feature of this human disease. The observed deficiency in activation leading to ND could be due to an inability to clear precursor and/or to generate sufficient product. Herein, we demonstrate that dietary supplementation with medium chain FA rescues ND in dbb mutants and partially rescues bgm mutants. In contrast, diet studies designed to increase the demand for product while leaving an accumulation of precursor unchanged enhance ND. Alternate approaches utilizing light/dark cycles, and blocking elongation of VLCFAs, corroborate these results demonstrating that a lack of activated FA product is causative of ND in bgm and dbb iv mutants. These data provide support to the observations that therapies designed to reduce toxic accumulations in patients with ALD are ineffective and instead suggest an alternate approach to providing the missing product. Consistent with this notion is our identification of a leukodystrophy patient harboring a rare mutation in a human homolog of bgm. Additionally this patient harbors a mutation in a known epilepsy gene suggesting that stress, by use or by trauma, may precipitate ND in an ACS mutant background. These data provide candidates for the long-hypothesized gene-gene and geneenvironment interactions proposed with ALD by identifying new genes (ACSs), mechanisms (lack of product), and environments (trauma, seizures) that contribute to disease. More broadly, these studies enhance our understanding of the required roles of lipids in the nervous system thereby contributing to knowledge of other lipid-mediated ND diseases.