ER responses play a key role in Swiss-Cheese/Neuropathy Target Esterase-associated neurodegeneration
| Autor: | Doris Kretzschmar, Alexander D. Law, Elizabeth R. Sunderhaus |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Endoplasmic Reticulum Unfolded protein response Animals Genetically Modified chemistry.chemical_compound 0302 clinical medicine Lipid homeostasis Drosophila Proteins Homeostasis Endoplasmic Reticulum Chaperone BiP Neurons Cell Death biology musculoskeletal neural and ocular physiology Neurodegeneration Endoplasmic Reticulum Stress Cell biology DNA-Binding Proteins Drosophila melanogaster Neurology Patatin-like phospholipase domain-containing protein 6 psychological phenomena and processes Locomotion Programmed cell death XBP1 SERCA Nerve Tissue Proteins Neuropathy target esterase Motor Activity Article lcsh:RC321-571 Sarcoplasmic Reticulum Calcium-Transporting ATPases 03 medical and health sciences medicine Animals lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Organophosphate-induced delayed neuropathy Endoplasmic reticulum fungi Tauroursodeoxycholic acid Sarco/endoplasmic reticulum Ca2+ ATPase Lipid Metabolism medicine.disease 030104 developmental biology Gene Expression Regulation chemistry Spastic paraplegia/ataxia Nerve Degeneration biology.protein 030217 neurology & neurosurgery |
| Zdroj: | Neurobiol Dis Neurobiology of Disease, Vol 130, Iss, Pp 104520-(2019) |
| ISSN: | 0969-9961 |
| DOI: | 10.1016/j.nbd.2019.104520 |
| Popis: | 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 response through the inhibition of the Sarco/Endoplasmic Reticulum Ca(2+) 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 sws(1), 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 sws(1). In addition, sws(1) flies showed reduced SERCA levels and expressing additional SERCA also suppressed the sws(1)-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 sws(1). This includes the effects on lipid composition because XBP1 and SERCA expression also reduced the LPC levels in sws(1). Promoting cytoprotective ER stress pathways may therefore provide a therapeutic approach to alleviate the neurodegeneration and motor symptoms seen in NTE-associated disorders. |
| Databáze: | OpenAIRE |
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