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Reduced oxidative stress suppresses neurotoxicity in the Drosophila model of TAF15-associated proteinopathies.

ABSTRACT: TATA-binding protein associated factor 15 (TAF15) is involved in the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TAF15 accumulates as cytoplasmic aggregates in neurons and the clearance of aggregates may be a therapeutic strategy for ALS, the underlying mechanisms of TAF15 in ALS remain poorly understood. Recently, we found that glutathione transferase omega 2 (GstO2) expression level is significantly reduced in the brain tissue of TAF15-expressing flies. In this study, we demonstrated that GstO2 overexpression in TAF15-induced flies rescues the locomotive activity and neuromuscular junctional defects. Furthermore, TAF15 levels in both cytoplasm and nuclear fractions significantly decreased in the heads of GstO2 co-expressing flies. GstO2-co-overexpression in neurons caused a marked decrease in intracellular reactive oxygen species generation in TAF15-induced flies. Our findings demonstrated that GstO2 was a pathogenic regulator of TAF15-associated proteinopathies. They help expand our understanding of TAF15-associated ALS pathogenesis.

SUBMITTER: Han YJ

PROVIDER: S-EPMC9677661 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Reduced oxidative stress suppresses neurotoxicity in the Drosophila model of TAF15-associated proteinopathies.

Han Yeo Jeong YJ Kim Kiyoung K

Molecular brain 20221121 1

TATA-binding protein associated factor 15 (TAF15) is involved in the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although TAF15 accumulates as cytoplasmic aggregates in neurons and the clearance of aggregates may be a therapeutic strategy for ALS, the underlying mechanisms of TAF15 in ALS remain poorly understood. Recently, we found that glutathione transferase omega 2 (GstO2) expression level is significantly reduced in the brain tissue of TAF15-expressin ...[more]

PMID: 36411469

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Project description:Both α-Synuclein (αSyn) accumulation and mitochondrial dysfunction have been implicated in the pathology of Parkinson's disease (PD). Although studies suggest that αSyn and its missense mutant, A53T, preferentially accumulate in the mitochondria, the mechanisms by which αSyn and mitochondrial proteins regulate each other to trigger mitochondrial and neuronal toxicity are poorly understood. ATP-dependent Clp protease (ClpP), a mitochondrial matrix protease, plays an important role in regulating mitochondrial protein turnover and bioenergetics activity. Here, we show that the protein level of ClpP is selectively decreased in αSyn-expressing cell culture and neurons derived from iPS cells of PD patient carrying αSyn A53T mutant, and in dopaminergic (DA) neurons of αSyn A53T mice and PD patient postmortem brains. Deficiency in ClpP induces an overload of mitochondrial misfolded/unfolded proteins, suppresses mitochondrial respiratory activity, increases mitochondrial oxidative damage and causes cell death. Overexpression of ClpP reduces αSyn-induced mitochondrial oxidative stress through enhancing the level of Superoxide Dismutase-2 (SOD2), and suppresses the accumulation of αSyn S129 phosphorylation and promotes neuronal morphology in neurons derived from PD patient iPS cells carrying αSyn A53T mutant. Moreover, we find that αSyn WT and A53T mutant interact with ClpP and suppress its peptidase activity. The binding of αSyn to ClpP further promotes a distribution of ClpP from soluble to insoluble cellular fraction in vitro and in vivo, leading to reduced solubility of ClpP. Compensating for the loss of ClpP in the substantia nigra of αSyn A53T mice by viral expression of ClpP suppresses mitochondrial oxidative damage, and reduces αSyn pathology and behavioral deficits of mice. Our findings provide novel insights into the mechanism underlying αSyn-induced neuronal pathology, and they suggest that ClpP might be a useful therapeutic target for PD and other synucleinopathies.

Project description:Classic galactosemia is a genetic disorder that results from profound loss of galactose-1P-uridylyltransferase (GALT). Affected infants experience a rapid escalation of potentially lethal acute symptoms following exposure to milk. Dietary restriction of galactose prevents or resolves the acute sequelae; however, many patients experience profound long-term complications. Despite decades of research, the mechanisms that underlie pathophysiology in classic galactosemia remain unclear. Recently, we developed a Drosophila melanogaster model of classic galactosemia and demonstrated that, like patients, GALT-null Drosophila succumb in development if exposed to galactose but live if maintained on a galactose-restricted diet. Prior models of experimental galactosemia have implicated a possible association between galactose exposure and oxidative stress. Here we describe application of our fly genetic model of galactosemia to the question of whether oxidative stress contributes to the acute galactose sensitivity of GALT-null animals. Our first approach tested the impact of pro- and antioxidant food supplements on the survival of GALT-null and control larvae. We observed a clear pattern: the oxidants paraquat and DMSO each had a negative impact on the survival of mutant but not control animals exposed to galactose, and the antioxidants vitamin C and α-mangostin each had the opposite effect. Biochemical markers also confirmed that galactose and paraquat synergistically increased oxidative stress on all cohorts tested but, interestingly, the mutant animals showed a decreased response relative to controls. Finally, we tested the expression levels of two transcripts responsive to oxidative stress, GSTD6 and GSTE7, in mutant and control larvae exposed to galactose and found that both genes were induced, one by more than 40-fold. Combined, these results implicate oxidative stress and response as contributing factors in the acute galactose sensitivity of GALT-null Drosophila and, by extension, suggest that reactive oxygen species might also contribute to the acute pathophysiology in classic galactosemia.

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Reduced oxidative stress suppresses neurotoxicity in the Drosophila model of TAF15-associated proteinopathies.

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Reduced oxidative stress suppresses neurotoxicity in the Drosophila model of TAF15-associated proteinopathies.

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