ER stress and the unfolded protein response in neurodegeneration

Hetz, Claudio; Saxena, Smita

doi:10.1038/nrneurol.2017.99

Cited by 752 publications

(702 citation statements)

References 189 publications

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“…XBP1 deficiency in motor neurons of SOD1 G93A mice also increases autophagy to clear mutant SOD1 aggregates, suggesting that XBP1s may contribute to ALS pathogenesis (Hetz et al 2009). Therefore, XBP1s has protective or detrimental effects on neurodegeneration, although the exact mechanism remains to be elucidated (Hetz and Saxena 2017).…”

Section: Xbp1mentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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Numerous environmental, physiological, and pathological insults disrupt protein-folding homeostasis in the endoplasmic reticulum (ER), referred to as ER stress. Eukaryotic cells evolved a set of intracellular signaling pathways, collectively termed the unfolded protein response (UPR), to maintain a productive ER protein-folding environment through reprogramming gene transcription and mRNA translation. The UPR is largely dependent on transcription factors (TFs) that modulate expression of genes involved in many physiological and pathological conditions, including development, metabolism, inflammation, neurodegenerative diseases, and cancer. Here we summarize the current knowledge about these mechanisms, their impact on physiological/pathological processes, and potential therapeutic applications.

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Section: Xbp1mentioning

confidence: 99%

Physiological/pathological ramifications of transcription factors in the unfolded protein response

2017

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“…With respect to physiology, chaperones resident on the membrane of ER guarantees the accurate folding of newly assembled proteins. Those perfectly folded proteins will be subsequently transported to Golgi apparatus, while those unfolded proteins will be sent to proteolytic processes for recycling, including ubiquitin–proteasome system and autophagic machinery (Hetz & Saxena, 2017). The accumulated misfolded proteins will trigger ER stress as well as its corresponding cellular response called unfolded protein response (UPR), which is a protective action to sustain cell survival.…”

Section: The Important Role Of Protein Synthesis Pathways In Cancer Amentioning

confidence: 99%

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

et al. 2018

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Pathways governing protein homeostasis are involved in maintaining the structural, quantitative, and functional stability of intracellular proteins and involve the ubiquitin–proteasome system, autophagy, endoplasmic reticulum, and mTOR pathway. Due to the broad physiological implications of protein homeostasis pathways, dysregulation of proteostasis is often involved in the development of multiple pathological conditions, including Alzheimer's disease (AD). Similar to other neurodegenerative diseases that feature pathogenic accumulation of misfolded proteins, Alzheimer's disease is characterized by two pathological hallmarks, amyloid‐β (Aβ) plaques and tau aggregates. Knockout or transgenic overexpression of various proteostatic components in mice results in AD‐like phenotypes. While both Aβ plaques and tau aggregates could in turn enhance the dysfunction of these proteostatic pathways, eventually leading to apoptotic or necrotic neuronal death and pathogenesis of Alzheimer's disease. Therefore, targeting the components of proteostasis pathways may be a promising therapeutic strategy against Alzheimer's disease.

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“…ER stress is implicated in many diseases, including multiple types of neural diseases [36,37]. More and more evidence suggests that ER stress plays an important role in hearing loss.…”

Section: Er Stress and Drug-induced Hearing Lossmentioning

confidence: 99%

Endoplasmic Reticulum Stress in Hearing Loss

Wang

2017

JOHBM

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Abstract:The endoplasmic reticulum (ER) plays important roles in coordinating protein biosynthesis and secretion in the cell. Accumulation of misfolded and/or unfolded proteins in the ER causes ER stress and the so-called unfolded protein response (UPR). The UPR alleviates ER stress through blocking protein synthesis and activating expression of chaperone genes, whereas prolonged UPR could induce cell death. Recent research has showed that ER stress and UPR are involved in hearing loss. Accordingly, animal experiments showed that chemical chaperones or ER stress inducers alleviate environment-related hearing loss, whereas ER stress inhibitor has been used to treat certain types of hereditary deafness. Further investigations are needed to fully understand the detailed mechanisms of how ER stress contributes to the loss of auditory function, which will help us to eventually develop ER-stress-related treatment of various types of deafness.

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ER stress and the unfolded protein response in neurodegeneration

Cited by 752 publications

References 189 publications

Physiological/pathological ramifications of transcription factors in the unfolded protein response

Physiological/pathological ramifications of transcription factors in the unfolded protein response

The emerging roles of protein homeostasis‐governing pathways in Alzheimer's disease

Endoplasmic Reticulum Stress in Hearing Loss

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