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Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
Alzheimer Disease ll: Pathophysiology01:23

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Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and microglia. Abnormal...
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Alzheimer disease is a chronic, progressive, and irreversible neurodegenerative disorder and the most common cause of dementia in older adults. It leads to gradual neuronal loss, causing cognitive decline, behavioral changes, and loss of functional independence.Risk Factors and EtiologyThe disease is multifactorial. Age is the strongest risk factor, with prevalence doubling every 5 years after age 65. Genetic factors include mutations in genes such as APP, PSEN1, and PSEN2, which are associated...
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In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
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Related Experiment Video

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Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
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Cell stress induces TDP-43 pathological changes associated with ERK1/2 dysfunction: implications in ALS.

Victòria Ayala1, Ana Belén Granado-Serrano, Daniel Cacabelos

  • 1Grup de Fisiopatologia Metabòlica, Departament de Medicina Experimental, Universitat de Lleida-IRBLleida, Lleida, Spain.

Acta Neuropathologica
|June 28, 2011
PubMed
Summary

Cellular stress triggers harmful TDP-43 changes in neurodegenerative diseases like ALS. This study reveals ERK1/2 as new players in ALS pathogenesis, linking cell stress to TDP-43 pathology.

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Cell Biology

Background:

  • TDP-43 protein mislocalization, phosphorylation, and aggregation are hallmarks of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).
  • The precise mechanisms initiating TDP-43 pathology and its relationship with cellular stress remain incompletely understood.

Purpose of the Study:

  • To investigate how chronic cellular stressors induce pathological changes in TDP-43.
  • To explore the role of the mitogen-activated protein kinase/extracellular signal-regulated kinases (ERK1/2) pathway in TDP-43-associated neurodegeneration.

Main Methods:

  • Utilized neuronal and spinal cord organotypic culture models.
  • Examined the effects of excitotoxicity, oxidative stress, proteasome dysfunction, and endoplasmic reticulum stress on TDP-43.
  • Investigated the presence and localization of TDP-43 and ERK1/2 in cellular stress models and ALS spinal cord tissues.

Main Results:

  • Chronic cellular stressors mechanistically induce TDP-43 mislocalization, phosphorylation, and aggregation, particularly in motor neurons.
  • Cellular stress leads to dysfunction in the ERK1/2 survival pathway, with cytosolic aggregates of ERK1/2 observed in stressed cells.
  • Abnormal phosphorylated ERK1/2 aggregates were found in ALS spinal cords, co-localizing with phosphorylated TDP-43 in motor neurons.

Conclusions:

  • Cellular stressors are critical factors driving neurodegeneration associated with TDP-43 pathology.
  • ERK1/2 is identified as a novel player in the pathogenesis of ALS, linking cellular stress to TDP-43 abnormalities.