title: Identification of dietary alanine toxicity and trafficking dysfunction in a Drosophila model of hereditary sensory and autonomic neuropathy type 1.
abstract: Hereditary sensory and autonomic neuropathy type 1 (HSAN1) is characterized by a loss of distal peripheral sensory and motorneuronal function, neuropathic pain and tissue necrosis. The most common cause of HSAN1 is due to dominant mutations in serine palmitoyl-transferase subunit 1 (SPT1). SPT catalyses the condensation of serine with palmitoyl-CoA, the initial step in sphingolipid biogenesis. Identified mutations in SPT1 are known to both reduce sphingolipid synthesis and generate catalytic promiscuity, incorporating alanine or glycine into the precursor sphingolipid to generate a deoxysphingoid base (DSB). Why either loss of function in SPT1, or generation of DSBs should generate deficits in distal sensory function remains unclear. To address these questions, we generated a Drosophila model of HSAN1. Expression of dSpt1 bearing a disease-related mutation induced morphological deficits in synapse growth at the larval neuromuscular junction consistent with a dominant-negative action. Expression of mutant dSpt1 globally was found to be mildly toxic, but was completely toxic when the diet was supplemented with alanine, when DSBs were observed in abundance. Expression of mutant dSpt1 in sensory neurons generated developmental deficits in dendritic arborization with concomitant sensory deficits. A membrane trafficking defect was observed in soma of sensory neurons expressing mutant dSpt1, consistent with endoplasmic reticulum (ER) to Golgi block. We found that we could rescue sensory function in neurons expressing mutant dSpt1 by co-expressing an effector of ER-Golgi function, Rab1 suggesting compromised ER function in HSAN1 affected dendritic neurons. Our Drosophila model identifies a novel strategy to explore the pathological mechanisms of HSAN1.
authors.affiliation: Department of Biology and Hull-York Medical School, University of York, York YO10 5DD, UK and.
authors.forename: Matthew C W
authors.initials: MC
authors.lastname: Oswald
authors.affiliation: Department of Biology and Hull-York Medical School, University of York, York YO10 5DD, UK and.
authors.forename: Ryan J H
authors.initials: RJ
authors.lastname: West
authors.affiliation: School of Biosciences, Cardiff University, Museum Avenue, Cardiff CF10 3AX, UK.
authors.forename: Emyr
authors.initials: E
authors.lastname: Lloyd-Evans
authors.affiliation: Department of Biology and Hull-York Medical School, University of York, York YO10 5DD, UK and sean.sweeney@york.ac.uk.
authors.forename: Sean T
authors.initials: ST
authors.lastname: Sweeney
mesh_terms: D000409:Alanine / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D004032:Diet; D004195:Disease Models, Animal; D004330:Drosophila; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020043:Genes, Essential; D017344:Genes, Insect; D006056:Golgi Apparatus / Q000378:metabolism; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008565:Membrane Proteins / Q000378:metabolism*; D009154:Mutation; D009469:Neuromuscular Junction / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D013107:Sphingolipids / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D013107:Sphingolipids; D000409:Alanine