Gordon HB, Valdez L, Letsou A. Etiology and treatment of adrenoleukodystrophy: new insights from Drosophila. Dis Model Mech. 2018 May 8. pii: dmm.031286. PMID: 29739804.
From the 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, cerebral X-ALD symptoms progress rapidly (in as little as two 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 adrenoleukodystrophy. 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 dABCD1 ... 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 flies prevents the onset of neurodegeneration. Taken together, our data provide new foundations both for diagnosing adrenoleukodystrophy and for designing effective, mechanism-based treatment protocols."
Showing posts with label Adrenoleukodystrophy. Show all posts
Showing posts with label Adrenoleukodystrophy. Show all posts
Thursday, May 10, 2018
Saturday, February 20, 2016
New double-mutant fly model of Adrenoleukodystrophy (ALD) "best paradigm to date"
Sivachenko A, Gordon HB, Kimball SS, Gavin EJ, Bonkowsky JL, Letsou A. Neurodegeneration in a Drosophila model of Adrenoleukodystrophy: the roles of the bubblegum and double bubble acyl-CoA synthetases. Dis Model Mech. 2016 Feb 18. pii: dmm.022244. PMID: 26893370.
From the abstract: "Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders ... novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants ... We show that the Drosophila bubblegum (bgm) and double bubble (dbb) genes have overlapping functions, and that the consequences of ... double knockout in the fly brain are profound ... providing the best paradigm to date for an animal model of Adrenoleukodystrophy (ALD), a fatal childhood neurodegenerative disease associated with the accumulation of very long chain fatty acids. ... in an extension of our model system to the study of human disease, we describe our identification of a leukodystrophy patient who harbors a rare mutation in a human homologue of Bgm and Dbb: the SLC27a6-encoded very-long-chain acyl-CoA synthetase."
From the abstract: "Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders ... novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants ... We show that the Drosophila bubblegum (bgm) and double bubble (dbb) genes have overlapping functions, and that the consequences of ... double knockout in the fly brain are profound ... providing the best paradigm to date for an animal model of Adrenoleukodystrophy (ALD), a fatal childhood neurodegenerative disease associated with the accumulation of very long chain fatty acids. ... in an extension of our model system to the study of human disease, we describe our identification of a leukodystrophy patient who harbors a rare mutation in a human homologue of Bgm and Dbb: the SLC27a6-encoded very-long-chain acyl-CoA synthetase."
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