Adrenoleukodystrophy (ALD) is a rare and oftentimes fatal progressive neurodegenerative disease. The most common form of the disease is X-linked (X-ALD);it occurs equally in all ethnic groups with an estimated incidence of 1:17,000. X-ALD is a clinically heterogeneous disorder, exhibiting incomplete penetrance and variable expressivity. The gene responsible for X-ALD has been cloned and shown to encode a peroxisomal half ATP-binding-cassette transporter (ABCD1). The 745 amino acid ABCD1 protein localizes to the peroxisomal membrane, where like other members of the ABC (ATP-binding cassette) transporter family, it functions to transport very long chain fatty acids (VLCFAs, 22 or more carbons) via their acyl-CoA esters into peroxisomes where they are degraded by ss-oxidation. Indeed, accumulation of saturated VLCFAs is a known biochemical hallmark of X-ALD. All X-ALD patients, including asymptomatic carriers show elevated levels of VLCFAs in the plasma, brain, and adrenal gland. Currently there are no good treatments for ALD, and the precise mechanisms through which VLCFA concentrations cause ALD are still unknown. Moreover, what previous controversial mouse and fly models of disease ignore is the potential redundancy within the transporter and synthetase gene families that control VLCFA metabolism. Thus, to better understand the evolution and overlapping biochemical functions of the many VLCFA synthetases in flies and humans, we turned to double mutant studies in Drosophila. We have shown that the consequences of knocking out duplicated VLCFA synthetase genes (bubblegum [bgm] and double bubble [dbb]) are profound, and have thus generated a potentially powerful animal model for ALD. From the perspective of disease etiology and treatment, our data indicate that bgm dbb -associated neurodegenerative disease is a disease of lipid- and membrane-rich cells, and that accumulation of fatty acids leads to cell death in affected areas of the brain. Here we propose to test whether the bgm dbb mutant accurately models ALD, with a long-term goal to ascertain a better cellular, molecular, genetic, and chemical understanding of ALD. In particular, we will determine whether bgm and dbb have cell autonomous roles in neurodegeneration and identify the cause(s) of cell death in cells of the CNS. In the longer term, we expect these studies will: (1) facilitate identification of other factors (genes) affecting VLCFA metabolism in the brains, and (2) permit screens for drugs effective in the treatment of neurodegeneration and ALD. ?2.
In our work, we utilize Drosophila as a model for studying the role of a metabolic enzyme (very long chain acyl-CoA synthetase [ACSVL]) in neurodegeneration and development. In particular, we are exploring the role of this enzyme in the pathogenesis of Adrenoleukodystrophy, a debilitating human condition in which very long chain fatty acid accumulation is correlated with extensive nervous system damage. References Cited ADDIN EN.REFLIST ?1. Min, K.T. &Benzer, S. Preventing neurodegeneration in the Drosophila mutant bubblegum [see comments]. Science 284, 1985-8 (1999). 2. Engelen, M. et al. Cholesterol-deprivation increases mono-unsaturated very long-chain fatty acids in skin fibroblasts from patients with X-linked adrenoleukodystrophy. Biochim Biophys Acta 1781, 105-11 (2008). 3. Kemp, S. et al. Gene redundancy and pharmacological gene therapy: implications for X-linked adrenoleukodystrophy. Nat Med 4, 1261-8 (1998). 4. Tschape, J.A. et al. The neurodegeneration mutant lochrig interferes with cholesterol homeostasis and Appl processing. Embo J 21, 6367-76 (2002). 5. Ito, M. et al. Potential environmental and host participants in the early white matter lesion of adreno-leukodystrophy: morphologic evidence for CD8 cytotoxic T cells, cytolysis of oligodendrocytes, and CD1-mediated lipid antigen presentation. J Neuropathol Exp Neurol 60, 1004-19 (2001). 6. Sarin, A. et al. Target cell lysis by CTL granule exocytosis is independent of ICE/Ced-3 family proteases. Immunity 6, 209-15 (1997). 7. Hein, S., Schonfeld, P., Kahlert, S. &Reiser, G. Toxic effects of X-linked adrenoleukodystrophy-associated, very long chain fatty acids on glial cells and neurons from rat hippocampus in culture. Hum Mol Genet 17, 1750-61 (2008). ? PAGE ? PHS 398/2590 (Rev. 11/07) Page PAGE ?1?Continuation Format Page
| Gordon, Hannah B; Valdez, Lourdes; Letsou, Anthea (2018) Etiology and treatment of adrenoleukodystrophy: new insights from Drosophila. Dis Model Mech 11: |
| Sivachenko, Anna; Gordon, Hannah B; Kimball, Suzanne S et al. (2016) Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles of the Bubblegum and Double bubble acyl-CoA synthetases. Dis Model Mech 9:377-87 |
| Gordon, Hannah B; Letsou, Anthea; Bonkowsky, Joshua L (2014) The leukodystrophies. Semin Neurol 34:312-20 |
