The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

Wodrich, Andrew P.K.; Scott, Andrew W.; Shukla, Arvind Kumar; Harris, Brent T.; Giniger, Edward

doi:10.3389/fnmol.2022.831116

Cited by 43 publications

(28 citation statements)

References 292 publications

(439 reference statements)

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“…The interference of misprocessed AGAL with the proper function of the ER, ERGIC, and TMED9 specifically, leads to the ER stress and activation of UPR, presumably triggering effects with pathogenic consequences on secretory active and/or post mitotic cell types. Similar dearrangements have been identified as primary in various monogenic glomerular and tubular diseases [24] endothelial dysfunction [31], cardiometabolic diseases [32], type 2 diabetes [33] and neurodegeneration [34].…”

Section: Discussionmentioning

confidence: 94%

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Živná

Dostálová

Barešová

et al. 2022

Preprint

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Background Classic Fabry disease (FD) is caused by GLA mutations that result in enzymatic deficiency of alpha-galactosidase A (AGAL), lysosomal storage of globotriaosylceramide, and a resulting multisystemic disease. In non-classic later-onset FD, patients have some preserved AGAL activity and a milder disease course, though female carriers may also be affected. While FD pathogenesis has been mostly attributed to catalytic deficiency of mutated AGAL, lysosomal storage and impairment of lysosomal functions, other pathogenic factors may be important, especially in non-classic later-onset FD. Methods We characterized the clinical, biochemical, genetic, molecular, cellular and organ pathology correlates of the p.L394P AGAL variant that was identified in six individuals with end-stage kidney disease by the Czech national screening program for FD and by further screening of 25 family members. Results Clinical findings revealed a milder clinical course with ~15% residual AGAL activity. Laboratory investigations documented intracellular retention of mutated AGAL with resulting ER stress and the unfolded protein response (UPR). Kidney biopsies did not show lysosomal storage. We observed similar findings of ER stress and UPR with several other classic and non-classic FD missense GLA variants. Conclusions We identified defective proteostasis of mutated AGAL resulting in chronic ER stress and UPR of AGAL expressing cells (hereafter referred to as AGALopathy) as an important contributor to FD pathogenesis. These findings provide insight into non-classic later-onset FD and may better explain clinical manifestations with implications for pathogenesis, clinical characterization and treatment of all FD forms.

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Section: Discussionmentioning

confidence: 94%

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

Živná

Dostálová

Barešová

et al. 2022

Preprint

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“…The diminished ability to maintain protein homeostasis is a hallmark of aging, and aged cells are unable to properly trigger UPR ER -related transcriptional responses [ 48 , 49 , 50 ]. Consistently, we demonstrated that the expression of several hepatic UPR ER -related genes, including Atf4 , was decreased in aged male WT mice.…”

Section: Discussionmentioning

confidence: 99%

SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice

Mizumoto

Yoshizawa

Sato

et al. 2022

Cells

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Sirtuins (SIRT1–7 in mammals) are evolutionarily conserved nicotinamide adenine dinucleotide-dependent lysine deacetylases/deacylases that regulate fundamental biological processes including aging. In this study, we reveal that male Sirt7 knockout (KO) mice exhibited an extension of mean and maximum lifespan and a delay in the age-associated mortality rate. In addition, aged male Sirt7 KO mice displayed better glucose tolerance with improved insulin sensitivity compared with wild-type (WT) mice. Fibroblast growth factor 21 (FGF21) enhances insulin sensitivity and extends lifespan when it is overexpressed. Serum levels of FGF21 were markedly decreased with aging in WT mice. In contrast, this decrease was suppressed in Sirt7 KO mice, and the serum FGF21 levels of aged male Sirt7 KO mice were higher than those of WT mice. Activating transcription factor 4 (ATF4) stimulates Fgf21 transcription, and the hepatic levels of Atf4 mRNA were increased in aged male Sirt7 KO mice compared with WT mice. Our findings indicate that the loss of SIRT7 extends lifespan and improves glucose metabolism in male mice. High serum FGF21 levels might be involved in the beneficial effect of SIRT7 deficiency.

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“…In addition, IRE1 cleaves and downregulates mRNAs and microRNAs (miRNAs) with its RNase domain through a process known as regulated IRE1-dependent decay (RIDD) [ 47 , 48 , 49 , 50 ]. RIDD decreases the load of nascent proteins entering the ER and is essential for maintaining ER homeostasis and cell survival.…”

Section: Upr Signalingmentioning

confidence: 99%

“…Growth arrest and DNA damage-inducible gene 34 (GADD34), which is positively regulated by phosphorylated eIF2α, is additionally transcriptionally induced by ATF4 and CHOP [ 54 ]. GADD34 is a modulatory subunit of the protein phosphatase 1C complex, which interacts to dephosphorylate eIF2α, thereby forming a negative feedback loop that restores protein synthesis [ 49 ]. Overall, PERK activation lessens the protein load in the ER, and, if the mechanisms involved are unable to restore ER homeostasis, PERK initiates cell death.…”

Section: Upr Signalingmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives

Yang

et al. 2022

Biomolecules

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The endoplasmic reticulum (ER) is an integral organelle for maintaining protein homeostasis. Multiple factors can disrupt protein folding in the lumen of the ER, triggering ER stress and activating the unfolded protein response (UPR), which interrelates with various damage mechanisms, such as inflammation, apoptosis, and autophagy. Numerous studies have linked ER stress and UPR to the progression of chronic obstructive pulmonary disease (COPD). This review focuses on the mechanisms of other cellular processes triggered by UPR and summarizes drug intervention strategies targeting the UPR pathway in COPD to explore new therapeutic approaches and preventive measures for COPD.

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The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

Cited by 43 publications

References 292 publications

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

AGAL misprocessing-induced ER stress and the unfolded protein response: lysosomal storage-independent mechanism of Fabry disease pathogenesis?

SIRT7 Deficiency Protects against Aging-Associated Glucose Intolerance and Extends Lifespan in Male Mice

Endoplasmic Reticulum Stress in Chronic Obstructive Pulmonary Disease: Mechanisms and Future Perspectives

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