ER responses play a key role in Swiss-Cheese/Neuropathy Target Esterase-associated neurodegeneration

Elizabeth R. Sunderhaus, Alexander D. Law, Doris Kretzschmar

Research output: Contribution to journalArticle

Abstract

Swiss Cheese (SWS) is the Drosophila orthologue of Neuropathy Target Esterase (NTE), a phospholipase that when mutated has been shown to cause a spectrum of disorders in humans that range from intellectual disabilities to ataxia. Loss of SWS in Drosophila also causes locomotion deficits, age-dependent neurodegeneration, and an increase in lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). SWS is localized to the Endoplasmic Reticulum (ER), and recently, it has been shown that perturbing the membrane lipid composition of the ER can lead to the activation of ER stress responses through the inhibition of the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA). To investigate whether ER stress induction occurs in NTE-associated disorders, we used the fly sws null mutant as a model. sws flies showed an activated ER stress response as determined by elevated levels of the chaperone GRP78 and by increased splicing of XBP, an ER transcription factor that activates transcriptional ER stress responses. To address whether ER stress plays a role in the degenerative and behavioral phenotypes detected in sws1, we overexpressed XBP1, or treated the flies with tauroursodeoxycholic acid (TUDCA), a chemical known to attenuate ER stress-mediated cell death. Both manipulations suppressed the locomotor deficits and neurodegeneration of sws1. In addition, sws1 flies showed reduced SERCA levels and expressing additional SERCA also suppressed the sws1-related phenotypes. This suggests that the disruption in lipid compositions and its effect on SERCA are inducing ER stress, aimed to ameliorate the deleterious effects of sws1. This includes the effects on lipid composition because XBP1 and SERCA expression also reduced the LPC levels in sws1. Promoting cytoprotective ER stress pathways may therefore provide a therapeutic approach to alleviate the neurodegeneration and motor symptoms seen in NTE-associated disorders.

Original languageEnglish (US)
Article number104520
JournalNeurobiology of Disease
Volume130
DOIs
StatePublished - Oct 1 2019

Fingerprint

Endoplasmic Reticulum Stress
Cheese
Endoplasmic Reticulum
Sarcoplasmic Reticulum Calcium-Transporting ATPases
Diptera
Lysophosphatidylcholines
Drosophila
Phenotype
Lipids
neurotoxic esterase
Phospholipases
Ataxia
Locomotion
Membrane Lipids
Phosphatidylcholines
Intellectual Disability
Cell Death
Transcription Factors

Keywords

  • Lipid homeostasis
  • Organophosphate-induced delayed neuropathy
  • Patatin-like phospholipase domain-containing protein 6
  • Sarco/endoplasmic reticulum Ca2+ ATPase
  • Spastic paraplegia/ataxia
  • Unfolded protein response

ASJC Scopus subject areas

  • Neurology

Cite this

ER responses play a key role in Swiss-Cheese/Neuropathy Target Esterase-associated neurodegeneration. / Sunderhaus, Elizabeth R.; Law, Alexander D.; Kretzschmar, Doris.

In: Neurobiology of Disease, Vol. 130, 104520, 01.10.2019.

Research output: Contribution to journalArticle

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abstract = "Swiss Cheese (SWS) is the Drosophila orthologue of Neuropathy Target Esterase (NTE), a phospholipase that when mutated has been shown to cause a spectrum of disorders in humans that range from intellectual disabilities to ataxia. Loss of SWS in Drosophila also causes locomotion deficits, age-dependent neurodegeneration, and an increase in lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). SWS is localized to the Endoplasmic Reticulum (ER), and recently, it has been shown that perturbing the membrane lipid composition of the ER can lead to the activation of ER stress responses through the inhibition of the Sarco/Endoplasmic Reticulum Ca2+ ATPase (SERCA). To investigate whether ER stress induction occurs in NTE-associated disorders, we used the fly sws null mutant as a model. sws flies showed an activated ER stress response as determined by elevated levels of the chaperone GRP78 and by increased splicing of XBP, an ER transcription factor that activates transcriptional ER stress responses. To address whether ER stress plays a role in the degenerative and behavioral phenotypes detected in sws1, we overexpressed XBP1, or treated the flies with tauroursodeoxycholic acid (TUDCA), a chemical known to attenuate ER stress-mediated cell death. Both manipulations suppressed the locomotor deficits and neurodegeneration of sws1. In addition, sws1 flies showed reduced SERCA levels and expressing additional SERCA also suppressed the sws1-related phenotypes. This suggests that the disruption in lipid compositions and its effect on SERCA are inducing ER stress, aimed to ameliorate the deleterious effects of sws1. This includes the effects on lipid composition because XBP1 and SERCA expression also reduced the LPC levels in sws1. Promoting cytoprotective ER stress pathways may therefore provide a therapeutic approach to alleviate the neurodegeneration and motor symptoms seen in NTE-associated disorders.",
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