Mediators of a long-term movement abnormality in a Drosophila melanogaster model of classic galactosemia

• Type of Material: Article
• Authors: Emily L. Ryan, Emory University; Brian DuBoff, Brigham and Women’s Hospital and Harvard Medical School; Mel B. Feany, Brigham and Women’s Hospital and Harvard Medical School; Judith Fridovich-Keil, Emory University
• Language: English
• Date: 2012-06-26
• Publisher: Company of Biologists
• Publication Version: Final Published Version
• Copyright Statement: © 2012 Ryan et al. Published by The Company of Biologists Ltd
• License: Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported
• Final Published Version (URL): http://dmm.biologists.org/content/5/6/796
• Title of Journal or Parent Work: Disease Models and Mechanisms
• ISSN: 1754-8403
• Volume: 5
• Issue: 6
• Start Page: 796
• End Page: 803
• Grant/Funding Information: This work was supported in part by the National Institutes of Health to J.L.F.-K. [grant number DK046403]; E.L.R. was supported in part by National Institutes of Health Training Grants [grant numbers T32 MH087977, TL1 RR025010 and T32 GM008367].
• Research Categories: Biology, Cell; Health Sciences, Pathology; Chemistry, Biochemistry

Abstract

Despite neonatal diagnosis and life-long dietary restriction of galactose, many patients with classic galactosemia grow to experience significant long-term complications. Among the more common are speech, cognitive, behavioral, ovarian and neurological/movement difficulties. Despite decades of research, the pathophysiology of these long-term complications remains obscure, hindering prognosis and attempts at improved intervention. As a first step to overcome this roadblock we have begun to explore long-term outcomes in our previously reported GALT-null Drosophila melanogaster model of classic galactosemia. Here we describe the first of these studies. Using a countercurrent device, a simple climbing assay, and a startle response test to characterize and quantify an apparent movement abnormality, we explored the impact of cryptic GALT expression on phenotype, tested the role of sublethal galactose exposure and galactose-1-phosphate (gal-1P) accumulation, tested the impact of age, and searched for potential anatomical defects in brain and muscle. We found that about 2.5% residual GALT activity was sufficient to reduce outcome severity. Surprisingly, sublethal galactose exposure and gal-1P accumulation during development showed no effect on the adult phenotype. Finally, despite the apparent neurological or neuromuscular nature of the complication we found no clear morphological differences between mutants and controls in brain or muscle, suggesting that the defect is subtle and/or is physiologic rather than structural. Combined, our results confirm that, like human patients, GALT-null Drosophila experience significant long-term complications that occur independently of galactose exposure, and serve as a proof of principle demonstrating utility of the GALT-null Drosophila model as a tool for exploring genetic and environmental modifiers of long-term outcome in GALT deficiency.