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Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models.
Hum Mol Genet. 2016 09 01; 25(17):3699-3714.HM

Abstract

The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1-phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signalling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbours, glycosylation losses, and differential changes in Wnt trans-synaptic signalling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signalling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology.

Authors+Show Affiliations

Department of Biological Sciences.Department of Biological Sciences.Department of Biological Sciences.Department of Biological Sciences kendal.broadie@vanderbilt.edu. Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

27466186

Citation

Jumbo-Lucioni, Patricia P., et al. "Coordinated Movement, Neuromuscular Synaptogenesis and Trans-synaptic Signaling Defects in Drosophila Galactosemia Models." Human Molecular Genetics, vol. 25, no. 17, 2016, pp. 3699-3714.
Jumbo-Lucioni PP, Parkinson WM, Kopke DL, et al. Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models. Hum Mol Genet. 2016;25(17):3699-3714.
Jumbo-Lucioni, P. P., Parkinson, W. M., Kopke, D. L., & Broadie, K. (2016). Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models. Human Molecular Genetics, 25(17), 3699-3714. https://doi.org/10.1093/hmg/ddw217
Jumbo-Lucioni PP, et al. Coordinated Movement, Neuromuscular Synaptogenesis and Trans-synaptic Signaling Defects in Drosophila Galactosemia Models. Hum Mol Genet. 2016 09 1;25(17):3699-3714. PubMed PMID: 27466186.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models. AU - Jumbo-Lucioni,Patricia P, AU - Parkinson,William M, AU - Kopke,Danielle L, AU - Broadie,Kendal, Y1 - 2016/07/27/ PY - 2016/01/21/received PY - 2016/06/28/revised PY - 2016/06/30/accepted PY - 2016/7/29/pubmed PY - 2017/8/24/medline PY - 2016/7/29/entrez SP - 3699 EP - 3714 JF - Human molecular genetics JO - Hum Mol Genet VL - 25 IS - 17 N2 - The multiple galactosemia disease states manifest long-term neurological symptoms. Galactosemia I results from loss of galactose-1-phosphate uridyltransferase (GALT), which converts galactose-1-phosphate + UDP-glucose to glucose-1-phosphate + UDP-galactose. Galactosemia II results from loss of galactokinase (GALK), phosphorylating galactose to galactose-1-phosphate. Galactosemia III results from the loss of UDP-galactose 4'-epimerase (GALE), which interconverts UDP-galactose and UDP-glucose, as well as UDP-N-acetylgalactosamine and UDP-N-acetylglucosamine. UDP-glucose pyrophosphorylase (UGP) alternatively makes UDP-galactose from uridine triphosphate and galactose-1-phosphate. All four UDP-sugars are essential donors for glycoprotein biosynthesis with critical roles at the developing neuromuscular synapse. Drosophila galactosemia I (dGALT) and II (dGALK) disease models genetically interact; manifesting deficits in coordinated movement, neuromuscular junction (NMJ) development, synaptic glycosylation, and Wnt trans-synaptic signalling. Similarly, dGALE and dUGP mutants display striking locomotor and NMJ formation defects, including expanded synaptic arbours, glycosylation losses, and differential changes in Wnt trans-synaptic signalling. In combination with dGALT loss, both dGALE and dUGP mutants compromise the synaptomatrix glycan environment that regulates Wnt trans-synaptic signalling that drives 1) presynaptic Futsch/MAP1b microtubule dynamics and 2) postsynaptic Frizzled nuclear import (FNI). Taken together, these findings indicate UDP-sugar balance is a key modifier of neurological outcomes in all three interacting galactosemia disease models, suggest that Futsch homolog MAP1B and the Wnt Frizzled receptor may be disease-relevant targets in epimerase and transferase galactosemias, and identify UGP as promising new potential therapeutic target for galactosemia neuropathology. SN - 1460-2083 UR - https://www.unboundmedicine.com/medline/citation/27466186/Coordinated_movement_neuromuscular_synaptogenesis_and_trans_synaptic_signaling_defects_in_Drosophila_galactosemia_models_ L2 - https://academic.oup.com/hmg/article-lookup/doi/10.1093/hmg/ddw217 DB - PRIME DP - Unbound Medicine ER -