The GRP78-PERK axis contributes to memory and synaptic impairments in Huntington's disease R6/1 mice

Espina, Marc; Di Franco, Nadia; Brañas-Navarro, Martina; Navarro, Irene Rodriguez; Brito, Veronica; Lopez-Molina, Laura; Costas-Insua, Carlos; Guzmán, Manuel; Ginés, Silvia

doi:10.1016/j.nbd.2023.106225

Cited by 7 publications

(4 citation statements)

References 73 publications

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“…Similar UPR signaling between diseases that lead to pathogenesis can be seen throughout neurodegenerative diseases and DM. In neurodegenerative diseases, stress can originate from the intracellular and extracellular aggregation of abnormally folded proteins 69,71,72,74,75,143 .…”

Section: Discussion: Upr Across Diseasesmentioning

confidence: 99%

“…This can be seen through pathological signaling of the IRE1 branch as well as chronic activation of the PERK-ATF4 pathway 69,145,146 . In Huntington's disease (HD), sustained UPR activation has been observed through elevated levels of GRP78, P-PERK, and P-elF2α, being directly associated with striatal neurodegeneration 143,146 . Hyperactivation of PERK can cause upregulation of GRP78, ultimately leading to hippocampal damage and memory impairment-hallmark symptoms of HD 143 .…”

Section: Discussion: Upr Across Diseasesmentioning

confidence: 99%

“…In Huntington's disease (HD), sustained UPR activation has been observed through elevated levels of GRP78, P-PERK, and P-elF2α, being directly associated with striatal neurodegeneration 143,146 . Hyperactivation of PERK can cause upregulation of GRP78, ultimately leading to hippocampal damage and memory impairment-hallmark symptoms of HD 143 . In Parkinson's disease, accumulation of αsynuclein activates the PERK pathway and participates in GRP78/BiP/α-synuclein binding in the ER, activating proapoptotic pathways 75 .…”

Section: Discussion: Upr Across Diseasesmentioning

confidence: 99%

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Unfolded Protein Response: From cellular stress to disease pathogenesis, with insights into platelet biology

Manoj,

Seetharam,

Krishnan

2024

Preprint

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Maintaining protein homeostasis, or proteostasis, is crucial for human health and disease prevention. The endoplasmic reticulum (ER) plays a central role in protein folding and processing, making it pivotal in this process. Disruptions in proteostasis result in ER stress, triggering the unfolded protein response (UPR), which involves key targets such as PERK-eIF2α, IRE1α-XBP1, and CRT. Notably, dysregulation of the UPR has been linked to disease progression in various conditions, including neurodegenerative disorders (such as ALS, Huntington's, and Parkinson's), diabetes, atherosclerosis, lung and kidney injuries, and numerous solid tumors. However, our understanding of the involvement of UPR in heme disorders such as multiple myeloma, neutropenia, and myeloproliferative neoplasms (MPNs) remains limited, highlighting a significant gap in research. In this review, we explore the role of the UPR in various diseases, with a particular focus on heme disorders, and discuss recent findings regarding platelet-specific UPR. Further investigation into the role of UPR in these heme disorders, along with the elucidation of cell-specific mechanisms underlying its pathological roles, holds promise for gaining insights into disease mechanisms and identifying potential therapeutic strategies.

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Section: Discussion: Upr Across Diseasesmentioning

confidence: 99%

Section: Discussion: Upr Across Diseasesmentioning

confidence: 99%

Section: Discussion: Upr Across Diseasesmentioning

confidence: 99%

See 1 more Smart Citation

Unfolded Protein Response: From cellular stress to disease pathogenesis, with insights into platelet biology

Manoj,

Seetharam,

Krishnan

2024

Preprint

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“…ER stress activation was observed in the early stages of HD in the hippocampus of R6/1 mice (HD models), evidenced by increased expression of GRP78 and CHOP. Spatial and recognition memory restoration occurred in R6/1 mice after inactivating PERK(Espina et al 2023 ). HD is characterized by the aggregation of toxic Huntington proteins.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Yuan,

She,

Jiang

et al. 2024

Mol Med

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The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways—inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER’s protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.

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Mild cognitive impairment in Huntington’s disease: challenges and outlooks

Jellinger

2024

J Neural Transm

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The GRP78-PERK axis contributes to memory and synaptic impairments in Huntington's disease R6/1 mice

Cited by 7 publications

References 73 publications

Unfolded Protein Response: From cellular stress to disease pathogenesis, with insights into platelet biology

Unfolded Protein Response: From cellular stress to disease pathogenesis, with insights into platelet biology

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer

Mild cognitive impairment in Huntington’s disease: challenges and outlooks

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