title: Coordinated movement, neuromuscular synaptogenesis and trans-synaptic signaling defects in Drosophila galactosemia models.
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.affiliation: Department of Biological Sciences.
authors.forename: Patricia P
authors.initials: PP
authors.lastname: Jumbo-Lucioni
authors.affiliation: Department of Biological Sciences.
authors.forename: William M
authors.initials: WM
authors.lastname: Parkinson
authors.affiliation: Department of Biological Sciences.
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Kopke
authors.affiliation: Department of Biological Sciences kendal.broadie@vanderbilt.edu.|Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA.
authors.forename: Kendal
authors.initials: K
authors.lastname: Broadie
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics; D005686:Galactokinase / Q000235:genetics*; D005693:Galactosemias / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006031:Glycosylation; D006801:Humans; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology*; D013569:Synapses / Q000378:metabolism / Q000502:physiology*; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase / Q000235:genetics*; D060449:Wnt Signaling Pathway
chemical_list: D029721:Drosophila Proteins; D005686:Galactokinase; D005694:UTP-Hexose-1-Phosphate Uridylyltransferase