Endoplasmic reticulum dysfunction in neurological disease

Roussel, Benoit D.; Kruppa, Antonina J.; Miranda, Elena; Crowther, Damian C.; Lomas, David A.; Marciniak, Stefan J.

doi:10.1016/s1474-4422(12)70238-7

Cited by 404 publications

(326 citation statements)

References 140 publications

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“…Chronic ER stress has been implicated in neuronal disorders causing neurodegeneration and cognitive dysfunction. [25][26][27][28] SCI causes increased levels of markers of ER stress, which is a known component of secondary injury. [29][30][31] However, no studies have examined whether or how SCI can induce ER stress responses in cortex or hippocampus or whether such changes may contribute to neurobehavioral consequences.…”

Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Zhao

Kumar

et al. 2016

Journal of Neurotrauma

105

100

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Clinical and experimental studies show that spinal cord injury (SCI) can cause cognitive impairment and depression that can significantly impact outcomes. Thus, identifying mechanisms responsible for these less well-examined, important SCI consequences may provide targets for more effective therapeutic intervention. To determine whether cognitive and depressive-like changes correlate with injury severity, we exposed mice to sham, mild, moderate, or severe SCI using the Infinite Horizon Spinal Cord Impactor and evaluated performance on a variety of neurobehavioral tests that are less dependent on locomotion. Cognitive impairment in Y-maze, novel objective recognition, and step-down fear conditioning tasks were increased in moderate-and severe-injury mice that also displayed depressive-like behavior as quantified in the sucrose preference, tail suspension, and forced swim tests. Bromo-deoxyuridine incorporation with immunohistochemistry revealed that SCI led to a long-term reduction in the number of newly-generated immature neurons in the hippocampal dentate gyrus, accompanied by evidence of greater neuronal endoplasmic reticulum (ER) stress. Stereological analysis demonstrated that moderate/severe SCI reduced neuronal survival and increased the number of activated microglia chronically in the cerebral cortex and hippocampus. The potent microglial activator cysteine-cysteine chemokine ligand 21 (CCL21) was elevated in the brain sites after SCI in association with increased microglial activation. These findings indicate that SCI causes chronic neuroinflammation that contributes to neuronal loss, impaired hippocampal neurogenesis and increased neuronal ER stress in important brain regions associated with cognitive decline and physiological depression. Accumulation of CCL21 in brain may subserve a pathophysiological role in cognitive changes and depression after SCI.

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Section: Introductionmentioning

confidence: 99%

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Zhao

Kumar

et al. 2016

Journal of Neurotrauma

105

100

View full text Add to dashboard Cite

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“…In addition, increasing evidence suggests that AD and OSA pathogenesis includes strong interactions with immunological mechanisms in the brain (Heneka et al, 2015a,b;Rosenzweig et al, 2015). Genome-wide analysis further suggest that several genes that increase the risk for sporadic AD also encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction (Heneka et al, 2015a) Comparably, abnormal protein folding and neuroinflammation have been also demonstrated or suggested by preclinical and clinical OSA studies (Roussel et al, 2013;Rosenzweig et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

The association between obstructive sleep apnea and Alzheimer's disease: a meta-analysis perspective

et al. 2017

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Alzheimer's disease (AD) and obstructive sleep apnea (OSA) are highly prevalent, chronic conditions with intriguing, yet poorly understood epidemiological overlap. To date, the amount of OSA syndrome present in patients with AD across literature remains unknown. To address this question, we collected all available published clinical data and analyzed them through a quantitative meta-analytical approach. The results of our quantitative meta-analysis suggest that the aggregate odds ratio for OSA in AD vs. healthy control was 5.05 and homogeneous. This reflects that patients with AD have a five times higher chance of presenting with OSA than cognitively non-impaired individuals of similar age. Moreover, these data suggest that around half of patients with AD have experienced OSA at some point after their initial diagnosis. The additive impact of progressive changes in sleep quality and structure, changes in cerebral blood flow and the cellular redox status in OSA patients may all be contributing factors to cognitive decline and may further aggravate AD progression. It is hoped that the high OSA rate in AD patients, as suggested by the findings of our meta-analysis, might provide a sufficient clinical incentive to alert clinicians the importance of screening patients for OSA in AD, and stimulate further research in this area.

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“…In regard to tau tangles, activated components of the UPR frequently co‐localize with hyperphosphorylated tau. Further mechanistic analyses have shown that phosphorylation of PERK activates its downstream kinase GSK‐3β, which in turn leads to the hyperphosphorylation of tau and facilitates the formation of tau tangles (Roussel, Kruppa, Miranda, Crowther, & Lomas, 2013). Meanwhile, due to the excessive burden on the ER, the UPR could also trigger apoptotic death of affected neurons, which is a vital mechanism of neuronal death in AD‐affected regions (Li, Yu, Jiang, & Tan, 2015; Xiang et al., 2017) (3; 5).…”

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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Endoplasmic reticulum dysfunction in neurological disease

Cited by 404 publications

References 140 publications

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

Endoplasmic Reticulum Stress and Disrupted Neurogenesis in the Brain Are Associated with Cognitive Impairment and Depressive-Like Behavior after Spinal Cord Injury

The association between obstructive sleep apnea and Alzheimer's disease: a meta-analysis perspective

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

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