FUS-induced neurotoxicity is prevented by inhibiting GSK-3β in a<i>Drosophila</i>model of amyotrophic lateral sclerosis

Choi, Hyun-Jun; Lee, Ji Young; Joo, Sun Hyung; Han, Yeo Jeong; Yoon, Ja Hoon; Kim, Ki‐Young

doi:10.1093/hmg/ddab290

Cited by 4 publications

(3 citation statements)

References 68 publications

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“…Notably, loss of function of sgg has been shown to rescue neuronal dysfunction in a TDP-43 Drosophila model 16,51 . Moreover, our findings are in line with Choi et al, who recently suggested that sgg inhibition could rescue various phenotypes in Drosophila overexpressing human FUS 52 . PP2A is a multi-subunit phosphatase highly expressed in the brain, of which PP2A-C (mts) is the catalytic subunit.…”

Section: Discussionsupporting

confidence: 92%

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

Tziortzouda,

Steyaert,

Scheveneels

et al. 2023

Preprint

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ALS is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of fALS cases. Studying the mechanisms by which mutant FUS is toxic to neurons may provide insight into the pathogenesis of both familial and sporadic forms of ALS. Here we identify Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALSin vivo, looking from fly to human. PP2A-C and GSK3β inhibition rescued FUS-induced toxicity inDrosophilaand disease-relevant phenotypes in human iPSC-derived spinal motor neurons (sMNs). In bothDrosophilaand human iPSC-sMNs, we observed reduced GSK3β inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3β hyperactivity. We found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation, and in synergy they modulate mitochondrial transport through the motor protein kinesin. Our data providein vivoevidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3 and kinesin in FUS-associated ALS.

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Section: Discussionsupporting

confidence: 92%

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

Tziortzouda,

Steyaert,

Scheveneels

et al. 2023

Preprint

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“…Notably, loss-of-function of sgg has been shown to rescue neuronal dysfunction in a TDP-43 Drosophila model [ 58 , 69 ]. Moreover, our findings are in line with Choi et al, who recently suggested that sgg inhibition could rescue various phenotypes in Drosophila overexpressing human FUS [ 10 ]. PP2A is a multi-subunit phosphatase highly expressed in the brain, of which PP2A-C (mts) is the catalytic subunit.…”

Section: Discussionsupporting

confidence: 92%

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

Tziortzouda,

Steyaert,

Scheveneels

et al. 2024

Acta Neuropathol

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease which currently lacks effective treatments. Mutations in the RNA-binding protein FUS are a common cause of familial ALS, accounting for around 4% of the cases. Understanding the mechanisms by which mutant FUS becomes toxic to neurons can provide insight into the pathogenesis of both familial and sporadic ALS. We have previously observed that overexpression of wild-type or ALS-mutant FUS in Drosophila motor neurons is toxic, which allowed us to screen for novel genetic modifiers of the disease. Using a genome-wide screening approach, we identified Protein Phosphatase 2A (PP2A) and Glycogen Synthase Kinase 3 (GSK3) as novel modifiers of FUS-ALS. Loss of function or pharmacological inhibition of either protein rescued FUS-associated lethality in Drosophila. Consistent with a conserved role in disease pathogenesis, pharmacological inhibition of both proteins rescued disease-relevant phenotypes, including mitochondrial trafficking defects and neuromuscular junction failure, in patient iPSC-derived spinal motor neurons (iPSC-sMNs). In FUS-ALS flies, mice, and human iPSC-sMNs, we observed reduced GSK3 inhibitory phosphorylation, suggesting that FUS dysfunction results in GSK3 hyperactivity. Furthermore, we found that PP2A acts upstream of GSK3, affecting its inhibitory phosphorylation. GSK3 has previously been linked to kinesin-1 hyperphosphorylation. We observed this in both flies and iPSC-sMNs, and we rescued this hyperphosphorylation by inhibiting GSK3 or PP2A. Moreover, increasing the level of kinesin-1 expression in our Drosophila model strongly rescued toxicity, confirming the relevance of kinesin-1 hyperphosphorylation. Our data provide in vivo evidence that PP2A and GSK3 are disease modifiers, and reveal an unexplored mechanistic link between PP2A, GSK3, and kinesin-1, that may be central to the pathogenesis of FUS-ALS and sporadic forms of the disease.

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“…In line with this, recent findings by Xu et al [92] demonstrate the strong implication of the Wnt/β-Catenin signalling pathway in cadmium-induced developmental neurotoxicity and neuroinflammation. GSK3B is involved in neurotoxicity induced by kainic acid [93] and FUS [94] and in TDP-43-mediated neurotoxicity [95].…”

Section: Common Proteins Involved In Temperature-induced Neurotoxicitymentioning

confidence: 99%

The Neurotoxic Effect of Environmental Temperature Variation in Adult Zebrafish (Danio rerio)

Maffioli,

Nonnis,

Grassi Scalvini

et al. 2023

IJMS

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Neurotoxicity consists of the altered functionality of the nervous system caused by exposure to chemical agents or altered chemical–physical parameters. The neurotoxic effect can be evaluated from the molecular to the behavioural level. The zebrafish Danio rerio is a model organism used in many research fields, including ecotoxicology and neurotoxicology. Recent studies by our research group have demonstrated that the exposure of adult zebrafish to low (18 °C) or high (34 °C) temperatures alters their brain proteome and fish behaviour compared to control (26 °C). These results showed that thermal variation alters the functionality of the nervous system, suggesting a temperature-induced neurotoxic effect. To demonstrate that temperature variation can be counted among the factors that generate neurotoxicity, eight different protein datasets, previously published by our research group, were subjected to new analyses using an integrated proteomic approach by means of the Ingenuity Pathway Analysis (IPA) software (Release December 2022). The datasets consist of brain proteome analyses of wild type adult zebrafish kept at three different temperatures (18 °C, 26 °C, and 34 °C) for 4 days (acute) or 21 days (chronic treatment), and of BDNF+/− and BDNF−/− zebrafish kept at 26 °C or 34 °C for 21 days. The results (a) demonstrate that thermal alterations generate an effect that can be defined as neurotoxic (p value ≤ 0.05, activation Z score ≤ −2 or ≥2), (b) identify 16 proteins that can be used as hallmarks of the neurotoxic processes common to all the treatments applied and (c) provide three protein panels (p value ≤ 0.05) related to 18 °C, 34 °C, and BDNF depletion that can be linked to anxiety-like or boldness behaviour upon these treatments.

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FUS-induced neurotoxicity is prevented by inhibiting GSK-3β in aDrosophilamodel of amyotrophic lateral sclerosis

Cited by 4 publications

References 68 publications

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

PP2A and GSK3 act as modifiers of FUS-ALS by modulating mitochondrial transport

The Neurotoxic Effect of Environmental Temperature Variation in Adult Zebrafish (Danio rerio)

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