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

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

doi:10.1016/j.nbd.2019.104520

Cited by 27 publications

(24 citation statements)

References 62 publications

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“…Nevertheless, PNPLA6 did suppress the locomotion and degenerative phenotypes of sws 1 . We previously obtained similar results by activating ER stress responses in sws 1 , which also reduced LPC levels but not PC levels, as well as suppressing behavioral and degenerative phenotypes (Sunderhaus et al, 2019). Together, these results suggest that the rise in LPC is more toxic than the increased PC.…”

Section: Resultssupporting

confidence: 67%

Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila

2019

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Mutations in patatin-like phospholipase domain-containing protein 6 (PNPLA6) have been linked with a number of inherited diseases with clinical symptoms that include spastic paraplegia, ataxia, and chorioretinal dystrophy. PNPLA6 is an evolutionary conserved protein whose ortholog in Drosophila is Swiss-Cheese (SWS). Both proteins are phospholipases hydrolyzing lysophosphatidylcholine (LPC) and phosphatidylcholine (PC). Consequently, loss of SWS/PNPLA6 in flies and mice increases both lipids and leads to locomotion deficits and neurodegeneration. PNPLA6 knock-out mice are embryonic lethal, and a mutation creating an early stop codon in human PNPLA6 has only been identified in compound heterozygote patients. In contrast, disease-causing point mutations are found in homozygous patients, with some localized in the phospholipase domain while others are in a region that contains several cNMP binding sites. To investigate how different mutations affect the function of PNPLA6 in an in vivo model, we expressed them in the Drosophila sws1 null mutant. Expressing wild-type PNPLA6 suppressed the locomotion and degenerative phenotypes in sws1 and restored lipid levels, confirming that the human protein can replace fly SWS. In contrast, none of the mutant proteins restored lipid levels, although they suppressed the behavioral and degenerative phenotypes, at least in early stages. These results show that these mutant forms of PNPLA6 retain some biological function, indicating that disruption of lipid homeostasis is only part of the pathogenic mechanism. Furthermore, our finding that mutations in the cNMP binding sites prevented the restoration of normal lipid levels supports previous evidence that cNMP regulates the phospholipase activity of PNPLA6.

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Section: Resultssupporting

confidence: 67%

Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila

2019

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“…Among the proteins identified, SERCA (EC 7.2.2.10) is an ion channel associated to Ca 2+ homeostasis and located in the ER. It balances calcium between the ER and the cytosol by pumping Ca 2+ into the ER in order to ensure proper protein folding and chaperone function (Britzolaki et al, 2020, Sunderhaus et al, 2019). Although its exact role in the central nervous system is not clear yet, it is known that SERCA-mediated Ca 2+ dyshomeostasis is associated with neuropathological conditions (Alvarez et al, 2020; Britzolaki et al, 2020).…”

Section: Resultsmentioning

confidence: 99%

“…Although its exact role in the central nervous system is not clear yet, it is known that SERCA-mediated Ca 2+ dyshomeostasis is associated with neuropathological conditions (Alvarez et al, 2020; Britzolaki et al, 2020). Several studies indicate that inhibition of SERCA function is related to neurodegeneration (Britzolaki et al, 2020; Sunderhaus et al, 2019), thus suggesting that this could be a major cause of PD (Alvarez et al, 2020). Therefore, we suspected that alterations of SERCA function caused by high carbonylation levels could be contributing to PD-related phenotypes in DJ-1β mutant flies as well as to PD physiopathology by affecting Ca 2+ homeostasis.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, SERCA dysfunction has been associated to ER stress and neuron loss in neurodegenerative disorders (Britzolaki et al, 2020). Consistently, it was shown that SERCA overexpression and/or pharmacological activation of this protein with small allosteric specific activators may alleviate ER stress (Kang et al, 2016;Sunderhaus et al, 2019). In fact, a small molecule activator of SERCA (CDN1163) was able to increase ER Ca 2+ content, to rescue neurons from ER stress-induced cell death in vitro, and to efficiently alleviate dyskinesia in the rat 6hydroxydopamine (6-OHDA) model of PD.…”

Section: Introductionmentioning

confidence: 83%

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SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Solana-Manrique

Muñoz-Soriano

et al. 2020

Preprint

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DJ-1 is a causative gene for familial Parkinson’s disease (PD) with different functions, standing out its role against oxidative stress (OS). Accordingly, PD model flies harboring a mutation in the DJ-1β gene (the Drosophila ortholog of human DJ-1) show high levels of OS markers like protein carbonylation, a common post-translational modification that may alter protein function. To increase our understanding of PD pathogenesis as well as to discover potential therapeutic targets for pharmacological intervention, we performed a redox proteomic assay in DJ-1β mutant flies. Among the proteins that showed increased carbonylation levels in PD model flies, we found SERCA, an endoplasmic reticulum Ca2+ channel that plays an important role in Ca2+ homeostasis. Several studies have supported the involvement of Ca2+ dyshomeostasis in PD. Interestingly, a functional link between DJ-1 and Ca2+ homeostasis maintenance was previously reported. Thus, we decided to study the relation between SERCA activity and PD physiopathology. Our results showed that SERCA enzymatic activity is significantly reduced in DJ-1β mutant flies, probably as a consequence of OS-induced carbonylation, as well as in a human cell PD model based on DJ-1-deficiency. Indeed, higher carbonylation levels of SERCA were also observed in DJ-1-deficient SH-SY5Y neuron-like cells compared to controls. In addition, we demonstrated that SERCA activity was increased in both PD models after treatment with a specific activator of this protein, CDN1163. Consistently, CDN1163 was also able to restore PD-related phenotypes in PD model flies and to increase viability in the human cell PD model. Taken together, our results indicate that impaired SERCA activity in both familial PD models may play a role in PD physiopathology. In addition, we demonstrate that therapeutic strategies addressing SERCA activation could be beneficial to treat this disease as shown for CDN1163.

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“…It has been well-demonstrated that lipid metabolism in glia is crucial for stress reaction under different conditions, primarily associated with oxidative stress [ 60 , 61 , 62 ]. Being a phospholipase [ 10 ], SWS plays an important role, not only for lipid metabolism, but also for stress regulation, thus providing cell metabolism and survival [ 63 ]. This could explain why the downregulation of sws in the case of KD results in ROS elevation in the brain, suggesting that a loss of the glia defense function occurs.…”

Section: Discussionmentioning

confidence: 99%

Morpho-Functional Consequences of Swiss Cheese Knockdown in Glia of Drosophila melanogaster

Ryabova

Melentev

Komissarov

et al. 2021

Cells

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Glia are crucial for the normal development and functioning of the nervous system in many animals. Insects are widely used for studies of glia genetics and physiology. Drosophila melanogaster surface glia (perineurial and subperineurial) form a blood–brain barrier in the central nervous system and blood–nerve barrier in the peripheral nervous system. Under the subperineurial glia layer, in the cortical region of the central nervous system, cortex glia encapsulate neuronal cell bodies, whilst in the peripheral nervous system, wrapping glia ensheath axons of peripheral nerves. Here, we show that the expression of the evolutionarily conserved swiss cheese gene is important in several types of glia. swiss cheese knockdown in subperineurial glia leads to morphological abnormalities of these cells. We found that the number of subperineurial glia nuclei is reduced under swiss cheese knockdown, possibly due to apoptosis. In addition, the downregulation of swiss cheese in wrapping glia causes a loss of its integrity. We reveal transcriptome changes under swiss cheese knockdown in subperineurial glia and in cortex + wrapping glia and show that the downregulation of swiss cheese in these types of glia provokes reactive oxygen species acceleration. These results are accompanied by a decline in animal mobility measured by the negative geotaxis performance assay.

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

Cited by 27 publications

References 62 publications

Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila

Disease-Associated PNPLA6 Mutations Maintain Partial Functions When Analyzed in Drosophila

SERCA activity is reduced inDJ-1mutant flies and human cells due to oxidative modification

Morpho-Functional Consequences of Swiss Cheese Knockdown in Glia of Drosophila melanogaster

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