Glutathione S-Transferase Rescues Motor Neuronal Toxicity in Fly Model of Amyotrophic Lateral Sclerosis

Joo, Sun Hyung; Han, Yeo Jeong; Choi, Hyun-Jun; Kim, Ki‐Young

doi:10.3390/antiox9070615

Cited by 9 publications

(9 citation statements)

References 22 publications

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“…Pan-neuronal overexpression of TDP-43 or TBPH induced premature lethality [ 266 , 274 , 275 , 306 , 307 ], reduced lifespan [ 266 , 305 , 309 , 310 ], larval locomotion defect [ 266 ], and age-dependent climbing deficit [ 309 , 311 ]. Similar phenotypes were observed when TBPH or TDP-43 was expressed in motoneurons [ 265 , 273 , 275 , 289 , 290 , 293 , 302 , 305 , 306 , 313 , 315 , 316 , 317 , 318 , 319 , 320 , 322 , 323 ]. By using the temporal and regional gene expression targeting (TARGET) system, it was shown that adult-restricted overexpression of TBPH or TDP-43 in all neurons or motoneurons induced age progressive climbing defects and reduced lifespan [ 288 , 301 , 305 , 307 , 312 , 324 ].…”

Section: Tdp-43 Proteinopathy In the Fruit Flysupporting

confidence: 66%

“…This indicates that the level of TDP-43 must be tightly regulated throughout life. GOF experiments also revealed that excess of TBPH or TDP-43 is highly toxic in muscles [ 270 , 306 , 307 ], glial cells [ 270 , 307 , 309 , 325 , 326 ], and in the eye [ 266 , 274 , 289 , 290 , 292 , 293 , 302 , 303 , 304 , 306 , 307 , 310 , 312 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 324 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 ]. Moreover, it was reported that TBPH or TDP-43 overexpression induces cell death, as was shown in motoneurons [ 266 , 289 , 290 , 301 ], glial cells [ 309 , 326 ], mushroom bodies [ 265 , 290 ], and in the eye.…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

“…This may explain some discrepancies between different GOF studies ( Table 9 and Table 10 ). Several phenotypes induced by TBPH /TDP-43 GOF, such as eye degeneration and climbing defects, show age-dependent progression [ 265 , 275 , 289 , 290 , 293 , 305 , 307 , 308 , 309 , 311 , 312 , 314 , 315 , 316 , 318 , 320 , 321 , 324 , 325 , 330 , 331 , 332 , 333 , 334 ]. As TBPH expression decreased with aging [ 338 ], one may speculate that reduced endogenous TBPH levels exacerbate GOF effects without excluding that phenotype aggravation may be due to continuous abnormal accumulation of TBPH /TDP-43.…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

“…Reduced lifespan [307,313] Age progressive climbing deficit [314] D42-Gal4 (motoneurons) Reduced survival, lethal at 2nd instar larval stage with high dose [315] Semi-lethal at 25 • C but viable at 18 • C, impaired climbing, no motoneuronal death in LIII ventral ganglia, motoneuronal death in adult thoracic ganglia [289] Larval locomotion defect [316] Increased larval turning [289,291,[317][318][319] Age progressive climbing deficit [305,308,316,320,321] Reduced lifespan [293,313,318,320,322,323] D42-Gal4, Tubulin-Gal80TS (motoneurons, induced at adult stage) Age progressive climbing deficit, reduced lifespan [324] OK371-Gal4 (glutamatergic neurons) Lethal [306] Lethal pupal, motoneuron death in LIII [290] OK371-Gal4/MARCM (individual leg motoneuron)…”

Section: Gal4 Line Phenotype/referencementioning

confidence: 99%

“…Neurodegeneration [310,312,316,317,319,320,324,[327][328][329] Age dependent progressive neurodegeneration [289,290,293,307,308,314,315,318,[330][331][332][333][334] GMR-Gal4, Tubulin-Gal80TS (eye, induced at adult stage) Age-dependent progressive neurodegeneration [293,312] Gal4 221 -Gal4 (sensory neurons) Promoted dendritic branching [274] OK107-Gal4 (mushroom bodies)…”

Section: Gmr-gal4 (Eye)mentioning

confidence: 99%

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Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Layalle

They

Ourghani

et al. 2021

IJMS

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Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with superoxide dismutase-1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP, encoding TDP-43) being the most frequent. In the last few decades, Drosophila melanogaster emerged as a versatile model for studying neurodegenerative diseases, including ALS. In this review, we describe the different Drosophila ALS models that have been successfully used to decipher the cellular and molecular pathways associated with SOD1, C9orf72, FUS, and TDP-43. The study of the known fruit fly orthologs of these ALS-related genes yielded significant insights into cellular mechanisms and physiological functions. Moreover, genetic screening in tissue-specific gain-of-function mutants that mimic ALS-associated phenotypes identified disease-modifying genes. Here, we propose a comprehensive review on the Drosophila research focused on four ALS-linked genes that has revealed novel pathogenic mechanisms and identified potential therapeutic targets for future therapy.

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Section: Tdp-43 Proteinopathy In the Fruit Flysupporting

confidence: 66%

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

Section: Gal4 Line Phenotype/referencementioning

confidence: 99%

Section: Gmr-gal4 (Eye)mentioning

confidence: 99%

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Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Layalle

They

Ourghani

et al. 2021

IJMS

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GSTO2 ameliorates human neuroblastoma cell apoptosis, inflammation, ferroptosis, and oxidative stress by upregulating GPX4 expression in intracerebral hemorrhage

Liu,

Tian,

Lei

2024

Drug Development Research

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Intracerebral hemorrhage (ICH) is a severe hemorrhagic stroke and induces severe secondary neurological injury. However, its pathogenesis remains to be explored. The present work investigates the role of glutathione S‐transferase omega 2 (GSTO2) in ICH and the underlying mechanism. Human neuroblastoma cells (SK‐N‐SH) were stimulated using hemin to mimic ICH‐like injury. Protein expression levels of GSTO2 and glutathione peroxidase 4 (GPX4) were detected by western blot analysis assay. Cell viability was assessed by cell counting kit‐8 assay. Cell proliferation was investigated by 5‐ethynyl‐2′‐deoxyuridine assay. Cell apoptosis was analyzed by flow cytometry. Interleukin‐6 and tumor necrosis factor‐α levels were quantified by enzyme‐linked immunosorbent assays. Fe2+ colorimetric assay kit was used to detect Fe2+ level. A cellular reactive oxygen species (ROS) assay kit was used to detect ROS levels. Malondialdehyde (MDA) level was assessed using the MDA content assay kit. GSH level was quantified using the GSH assay kit. Co‐immunoprecipitation assay was performed to identify the association between GSTO2 and GPX4. Hemin stimulation suppressed SK‐N‐SH cell proliferation and promoted cell apoptosis, cell inflammation, ferroptosis, and oxidative stress. GSTO2 expression was downregulated in hemin‐treated SK‐N‐SH cells in comparison with the control group. In addition, ectopic GSTO2 expression counteracted hemin‐induced inhibitory effect on cell proliferation and promoting effects on cell apoptosis, inflammation, ferroptosis, and oxidative stress. Moreover, GSTO2 was associated with GPX4 in SK‐N‐SH cells. GPX4 silencing attenuated GSTO2 overexpression‐induced effects on hemin‐stimulated SK‐N‐SH cell injury. GSTO2 ameliorated SK‐N‐SH cell apoptosis, inflammation, ferroptosis, and oxidative stress by upregulating GPX4 expression in ICH, providing a therapeutic strategy for ICH.

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