Neuroprotective modulation of the unfolded protein response in Marinesco-Sjögren syndrome: PERK signaling inhibition and beyond

Restelli, Elena; Masone, Antonio; Sallese, Michele; Chiesa, Roberto

doi:10.4103/1673-5374.243708

Cited by 5 publications

(8 citation statements)

References 11 publications

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“…We hypothesized that partial translational recovery by trazodone or DBM might even provide better neuroprotection than GSK2606414 by preventing overloading the inefficient ER folding machinery of SIL1-deficient Purkinje cells (12). We also tested TUDCA, a chemical chaperone previously shown to alleviate ER stress-induced toxicity in a MSS cell model, as a potential candidate for combination therapy with PERK inhibitors to enhance neuroprotection (12). Since trazodone, DBM and TUDCA are suitable for clinical use, positive outcomes in the woozy mouse model might have supported their repositioning for the treatment of MSS.…”

Section: Discussionmentioning

confidence: 99%

“…However, GSK2606414 is toxic to the pancreas and does not provide complete neuroprotection, possibly because full translational recovery due to complete PERK inhibition overloads the inefficient folding machinery of SIL1-deficient cells. It may be necessary to fine-tune PERK signaling and boost protein folding in the ER for better effects (3,12).…”

Section: Introductionmentioning

confidence: 99%

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Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice

Lavigna,

Grasso,

Pasini

et al. 2024

Preprint

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There is no cure for Marinesco-Sjögren syndrome (MSS), a genetic multisystem disease linked to loss-of-function mutations in the SIL1 gene, encoding a BiP co-chaperone. We previously found that the PERK kinase inhibitor GSK2606414 delayed cerebellar Purkinje cell (PC) degeneration and the onset of ataxia in the woozy mouse model of MSS. However, GSK2606414 is toxic to the pancreas and does not completely rescue the woozy phenotype. The present study tested trazodone and dibenzoylmethane (DBM), which partially inhibit PERK signaling with neuroprotective effects and no pancreatic toxicity. We also tested the chemical chaperone tauroursodeoxycholic acid (TUDCA), which can protect MSS patients' cells from stress-induced apoptosis. Mice were chronically treated for five weeks, starting from a presymptomatic stage. Trazodone was given 40 mg/kg daily by intraperitoneal (ip) injection. DBM was given 0.5% in the diet ad libitum. TUDCA was given either 0.4% in the diet, or 500 mg/kg ip every three days. None of the treatments prevented motor dysfunction in woozy mice, assessed by the beam walking and rotarod tests. Only trazodone slightly boosted beam walking performance. However, immunohistochemistry found no reduction in the number of CHOP-positive PCs, or increased PC survival, indicating no neuroprotective inhibition of PERK signaling. Pharmacokinetic studies excluded that the lack of effect was due to altered drug metabolism in woozy mice. These results indicate that trazodone, DBM and TUDCA, at dosing regimens active in other neurodegenerative disease mouse models, have no disease-modifying effect in a preclinical model of MSS.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice

Lavigna,

Grasso,

Pasini

et al. 2024

Preprint

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“…It crosses the blood‐brain barrier, and is being tested, alone or in combination therapies, in a number of clinical trials for protein‐misfolding diseases such as ALS. It may be interesting to see whether TUDCA has beneficial effects in the woozy model, and if combining TUDCA with trazodone or DBM provides better neuroprotection than PERK signalling inhibitors alone The use of compounds already approved for use in humans could facilitate rapid translation to the clinic. Since carriers of SIL1 mutations can be identified by molecular genetic screening prenatally or soon after birth, treatment could be started before the disease onset, increasing the chance of success.…”

Section: Discussionmentioning

confidence: 99%

Review: Protein misfolding diseases – the rare case of Marinesco‐Sjögren syndrome

Chiesa

Sallese

2020

Neuropathology Appl Neurobio

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Secretory and cell membrane proteins are synthesized in the endoplasmic reticulum (ER), where a network of molecular chaperones and folding factors ensure correct protein folding and export to post‐ER compartments. Failure of this process leads to accumulation of unfolded/misfolded proteins, ER stress, and activation of the unfolded protein response (UPR), a complex signalling pathway aimed at restoring ER homeostasis, whose failure eventually leads to cell death. Suppressor of Ire1/Lhs1 double mutant (SIL1) is a nucleotide exchange factor for immunoglobulin binding protein, the main ER chaperone and primary sensor of ER stress. Loss of SIL1 function causes Marinesco‐Sjögren syndrome (MSS), a rare multisystem disease of early infancy for which there is no cure. This review, examines the current understanding of SIL1 activities in the ER, and reviews experimental data describing the consequences of SIL1 deficiency in cell and animal models. We discuss the evidence supporting a role of the UPR – particularly the protein kinase RNA‐like endoplasmic reticulum kinase branch – in the pathogenesis of MSS, and how this may be pharmacologically manipulated for treatment.

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“…The mechanisms by which SIL1 mutations cause MSS are not yet fully understood, but loss of SIL1 protein with disruption of ER proteostasis and maladaptive UPR may contribute to the pathogenic process. We found that the PERK inhibitor GSK2606414 partially restores proteostasis, attenuates apoptosis in SIL1-deficient cells, and has beneficial effects in the woozy mouse model of MSS, attenuating PC degeneration and muscle pathology [14][15][16]. Another study showed that the chemical chaperone tauroursodeoxycholic acid (TUDCA) slightly attenuates ER stress-induced apoptosis in MSS patients' lymphoblastoid cells [17].…”

Section: Introductionmentioning

confidence: 98%

Proteomic Analysis of Marinesco–Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss

Potenza

Cufaro

Biase

et al. 2021

IJMS

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Marinesco–Sjogren syndrome (MSS) is a rare multisystem pediatric disorder, caused by loss-of-function mutations in the gene encoding the endoplasmic reticulum cochaperone SIL1. SIL1 acts as a nucleotide exchange factor for BiP, which plays a central role in secretory protein folding. SIL1 mutant cells have reduced BiP-assisted protein folding, cannot fulfil their protein needs, and experience chronic activation of the unfolded protein response (UPR). Maladaptive UPR may explain the cerebellar and skeletal muscle degeneration responsible for the ataxia and muscle weakness typical of MSS. However, the cause of other more variable, clinical manifestations, such as mild to severe mental retardation, hypogonadism, short stature, and skeletal deformities, is less clear. To gain insights into the pathogenic mechanisms and/or adaptive responses to SIL1 loss, we carried out cell biological and proteomic investigations in skin fibroblasts derived from a young patient carrying the SIL1 R111X mutation. Despite fibroblasts not being overtly affected in MSS, we found morphological and biochemical changes indicative of UPR activation and altered cell metabolism. All the cell machineries involved in RNA splicing and translation were strongly downregulated, while protein degradation via lysosome-based structures was boosted, consistent with an attempt of the cell to reduce the workload of the endoplasmic reticulum and dispose of misfolded proteins. Cell metabolism was extensively affected as we observed a reduction in lipid synthesis, an increase in beta oxidation, and an enhancement of the tricarboxylic acid cycle, with upregulation of eight of its enzymes. Finally, the catabolic pathways of various amino acids, including valine, leucine, isoleucine, tryptophan, lysine, aspartate, and phenylalanine, were enhanced, while the biosynthetic pathways of arginine, serine, glycine, and cysteine were reduced. These results indicate that, in addition to UPR activation and increased protein degradation, MSS fibroblasts have profound metabolic alterations, which may help them cope with the absence of SIL1.

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Neuroprotective modulation of the unfolded protein response in Marinesco-Sjögren syndrome: PERK signaling inhibition and beyond

Cited by 5 publications

References 11 publications

Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice

Trazodone, dibenzoylmethane and tauroursodeoxycholic acid do not prevent motor dysfunction and neurodegeneration in Marinesco-Sjögren syndrome mice

Review: Protein misfolding diseases – the rare case of Marinesco‐Sjögren syndrome

Proteomic Analysis of Marinesco–Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss

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