Cell Death and Neurodegeneration

Andreone, Benjamin J.; Larhammar, Martin; Lewcock, Joseph W.

doi:10.1101/cshperspect.a036434

Cited by 77 publications

(53 citation statements)

References 167 publications

(183 reference statements)

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“…The extent of ER stress and the ability to compensate it results in a selective role of the UPR, either pro-adaptive or proapoptotic. In case of failure in bringing the cell to homeostasis by the above methods, the UPR triggers initiation of programmed cell death or apoptosis [11,12].…”

Section: The Unfolded Protein Responsementioning

confidence: 99%

“…Therefore, depletion of neurons due to cell death results in neurodegeneration, a loss of neuronal function in central nervous system tissues. Some of the best known examples of neurodegenerative diseases are AD, PD, HD, ALS, Prion Disease and tauopathies such as Progressive Supranuclear Palsy (PSP) and Frontotemporal Dementia (FTD) [11].…”

Section: Er Stress In Neurodegenerative Diseasesmentioning

confidence: 99%

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PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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With the extension of life span in recent decades, there is an increasing burden of late-onset neurodegenerative diseases, for which effective treatments are lacking. Neurodegenerative diseases include the widespread Alzheimer’s disease (AD) and Parkinson’s disease (PD), the less frequent Huntington’s disease (HD) and Amyotrophic Lateral Sclerosis (ALS) and also rare early-onset diseases linked to mutations that cause protein aggregation or loss of function in genes that maintain protein homeostasis. The difficulties in applying gene therapy approaches to tackle these diseases is drawing increasing attention to strategies that aim to inhibit cellular toxicity and restore homeostasis by intervening in cellular pathways. These include the unfolded protein response (UPR), activated in response to endoplasmic reticulum (ER) stress, a cellular affliction that is shared by these diseases. Special focus is turned to the PKR-like ER kinase (PERK) pathway of the UPR as a target for intervention. However, the complexity of the pathway and its ability to promote cell survival or death, depending on ER stress resolution, has led to some confusion in conflicting studies. Both inhibition and activation of the PERK pathway have been reported to be beneficial in disease models, although there are also some reports where they are counterproductive. Although with the current knowledge a definitive answer cannot be given on whether it is better to activate or to inhibit the pathway, the most encouraging strategies appear to rely on boosting some steps without compromising downstream recovery.

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Section: The Unfolded Protein Responsementioning

confidence: 99%

Section: Er Stress In Neurodegenerative Diseasesmentioning

confidence: 99%

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

2021

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“…Neuronal cell death can occur through multiple mechanisms in settings of trauma, ischemia, or disease [ 1 , 2 ]. In settings that involve progressive neurodegeneration such as alcohol use disorder (AUD), aging, or Alzheimer’s disease, the underlying cell death mechanisms can be more difficult to identify.…”

Section: Introductionmentioning

confidence: 99%

TRAIL Mediates Neuronal Death in AUD: A Link between Neuroinflammation and Neurodegeneration

Qin

Zou

Barnett

et al. 2021

IJMS

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Although the cause of progressive neurodegeneration is often unclear, neuronal death can occur through several mechanisms. In conditions such as Alzheimer’s or alcohol use disorder (AUD), Toll-like receptor (TLR) induction is observed with neurodegeneration. However, links between TLR activation and neurodegeneration are lacking. We report a role of apoptotic neuronal death in AUD through TLR7-mediated induction of death receptor signaling. In postmortem human cortex, a two-fold increase in apoptotic terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in neurons was found in AUD versus controls. This occurred with the increased expression of TLR7 and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) death receptors. Binge ethanol treatment in C57BL/6 mice increased TLR7 and induced neuronal apoptosis in cortical regions that was blocked by TLR7 antagonism. Mechanistic studies in primary organotypic brain slice culture (OBSC) found that the inhibition of TLR7 and its endogenous ligand let-7b blocked ethanol-induced neuronal cell death. Both IMQ and ethanol induced the expression of TRAIL and its death receptor. In addition, TRAIL-neutralizing monoclonal antibodies blocked both imiquimod (IMQ) and ethanol induced neuronal death. These findings implicate TRAIL as a mediator of neuronal apoptosis downstream of TLR7 activation. TLR7 and neuronal apoptosis are implicated in other neurodegenerative diseases, including Alzheimer’s disease. Therefore, TRAIL may represent a therapeutic target to slow neurodegeneration in multiple diseases.

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“…Primary inherited but also adult mitochondrial dysfunctions in neurons are not only linked to mtDNA or mtRNA changes but also to disrupted Krebs cycle, and related biochemical pathways up to reduced ATP availability. Therefore, altered morphology and signaling of crucial organelles, like mitochondria and lysosomes, dramatically initiate neurodegeneration ( Lee et al, 2018 ; Cowan et al, 2019 ; Lie and Nixon, 2019 ) and vulnerable neurons’ death ( Andreone et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Natural Compounds and Autophagy: Allies Against Neurodegeneration

Stacchiotti

Corsetti

2020

Front. Cell Dev. Biol.

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Prolonging the healthy life span and limiting neurological illness are imperative goals in gerontology. Age-related neurodegeneration is progressive and leads to severe diseases affecting motility, memory, cognitive function, and social life. To date, no effective treatments are available for neurodegeneration and irreversible neuronal loss. Bioactive phytochemicals could represent a natural alternative to ensure active aging and slow onset of neurodegenerative diseases in elderly patients. Autophagy or macroautophagy is an evolutionarily conserved clearing process that is needed to remove aggregateprone proteins and organelles in neurons and glia. It also is crucial in synaptic plasticity. Aberrant autophagy has a key role in aging and neurodegeneration. Recent evidence indicates that polyphenols like resveratrol and curcumin, flavonoids, like quercetin, polyamine, like spermidine and sugars, like trehalose, limit brain damage in vitro and in vivo. Their common mechanism of action leads to restoration of efficient autophagy by dismantling misfolded proteins and dysfunctional mitochondria. This review focuses on the role of dietary phytochemicals as modulators of autophagy to fight Alzheimer's and Parkinson's diseases, fronto-temporal dementia, amyotrophic lateral sclerosis, and psychiatric disorders. Currently, most studies have involved in vitro or preclinical animal models, and the therapeutic use of phytochemicals in patients remains limited.

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Cell Death and Neurodegeneration

Cited by 77 publications

References 167 publications

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

PERK Pathway and Neurodegenerative Disease: To Inhibit or to Activate?

TRAIL Mediates Neuronal Death in AUD: A Link between Neuroinflammation and Neurodegeneration

Natural Compounds and Autophagy: Allies Against Neurodegeneration

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