Endoplasmic Reticulum Stress and Unfolded Protein Response in Neurodegenerative Diseases

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(17), P. 6127 - 6127

Published: Aug. 25, 2020

The endoplasmic reticulum (ER) is an important organelle involved in protein quality control and cellular homeostasis. accumulation of unfolded proteins leads to ER stress, followed by adaptive response via the activation (UPR), PKR-like kinase (PERK), inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α) activating transcription factor 6 (ATF6) pathways. However, prolonged cell stress activates apoptosis signaling leading death. Neuronal cells are particularly sensitive misfolding, consequently UPR dysfunctions were found be many neurodegenerative diseases including Alzheimer’s disease, Parkinson’s amyotrophic lateral sclerosis prions diseases, among others characterized aggregation misfolded proteins. Pharmacological modulation affected tissues may contribute treatment prevention neurodegeneration. association between neuropathology well established. In this review, we provide up-to-date evidence disorders therapeutic strategies targeting ameliorating toxic effects unfolding aggregation.

Language: Английский

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Ubiquitination-Proteasome System (UPS) and Autophagy Two Main Protein Degradation Machineries in Response to Cell Stress

Cells, Journal Year: 2022, Volume and Issue: 11(5), P. 851 - 851

Published: March 1, 2022

In response to environmental stimuli, cells make a series of adaptive changes combat the injury, repair damage, and increase tolerance stress. However, once damage is too serious repair, will undergo apoptosis protect overall through suicidal behavior. Upon external stimulation, some intracellular proteins turn into unfolded or misfolded protein, exposing their hydrophobic regions form protein aggregation, which may ultimately produce cells. Ubiquitin plays an important role in degradation these unnatural by tagging with ubiquitin chains ubiquitin-proteasome autophagy system. If two processes fail eliminate abnormal aggregates, move death. Dysregulation system (UPS) result development numerous diseases. This review focuses on molecular mechanisms UPS clearance relationship between dysregulation network

Language: Английский

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Alpha-Synuclein Physiology and Pathology: A Perspective on Cellular Structures and Organelles

Frontiers in Neuroscience, Journal Year: 2020, Volume and Issue: 13

Published: Jan. 23, 2020

Alpha-synuclein (α-syn) is localized in cellular organelles of most neurons, but many its physiological functions are only partially understood. α-syn accumulation associated with Parkinson's disease, dementia Lewy bodies and multiple system atrophy as well others synucleinopathies, however, the exact pathomechanisms that underlie these neurodegenerative diseases remain elusive. In this review, we describe what known about function pathophysiological changes different structures organelles, including behavior a prion-like protein. We summarize current knowledge pathological forms, covering effect on each organelle, aggregation toxicity model systems, special interest mitochondria due to relevance during apoptotic process dopaminergic neurons. Moreover, explore exert by interacting chromatin remodeling proteins add or remove histone marks, upregulates own expression resume impairment induce vesicular traffic endoplasmic reticulum. then recapitulate events lead Golgi apparatus fragmentation, caused presence α-syn. Finally, report recent findings α-syn, indirectly produced endolysosomal system. conclusion, important steps into understanding have been made using vivo vitro models, time right start integrating observational studies mechanistic models interactions, order look at more complete picture processes underlying α-synucleinopathies.

Language: Английский

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Plasma proteomics identify biomarkers predicting Parkinson’s disease up to 7 years before symptom onset

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 18, 2024

Abstract Parkinson’s disease is increasingly prevalent. It progresses from the pre-motor stage (characterised by non-motor symptoms like REM sleep behaviour disorder), to disabling motor stage. We need objective biomarkers for early/pre-motor stages be able intervene and slow underlying neurodegenerative process. Here, we validate a targeted multiplexed mass spectrometry assay blood samples recently diagnosed patients ( n = 99), individuals with isolated disorder (two cohorts: 18 54 longitudinally), healthy controls 36). Our machine-learning model accurately identifies all Parkinson classifies 79% of up 7 years before onset analysing expression eight proteins—Granulin precursor, Mannan-binding-lectin-serine-peptidase-2, Endoplasmatic-reticulum-chaperone-BiP, Prostaglaindin-H2-D-isomaerase, Interceullular-adhesion-molecule-1, Complement C3, Dickkopf-WNT-signalling pathway-inhibitor-3, Plasma-protease-C1-inhibitor. Many these correlate symptom severity. This specific panel indicates molecular events in early could help identify at-risk participants clinical trials aimed at slowing/preventing disease.

Language: Английский

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Alpha-Synuclein Post-translational Modifications: Implications for Pathogenesis of Lewy Body Disorders

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: June 25, 2021

Lewy Body Disorders (LBDs) lie within the spectrum of age-related neurodegenerative diseases now frequently categorized as synucleinopathies. LBDs are considered to be among second most common form dementias after Alzheimer's disease. They progressive conditions with variable clinical symptoms embodied specific cognitive and behavioral disorders. There currently no effective treatments for LBDs. histopathologically characterized by presence abnormal neuronal inclusions commonly known Bodies (LBs) extracellular Neurites (LNs). The predominantly comprise aggregates alpha-synuclein (aSyn). It has been proposed that post-translational modifications (PTMs) such aSyn phosphorylation, ubiquitination SUMOylation, Nitration, o-GlcNacylation, Truncation play important roles in formation toxic forms protein, which consequently facilitates these inclusions. This review focuses on role different PTMs pathogenesis We highlight how interact promote misfolding aggregation interplay cell membranes leading potential functional pathogenic consequences detected so far, their involvement development

Language: Английский

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Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism

Molecular Psychiatry, Journal Year: 2021, Volume and Issue: 27(3), P. 1310 - 1321

Published: Dec. 14, 2021

Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure available would stop the dopaminergic decline or restore function of injured PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins promote neuron survival during mammalian development and regulate adult neuronal plasticity, they studied as potential therapeutic agents for treatment diseases. However, results from clinical trials GDNF related NTF neurturin (NRTN) PD have been modest so far. In this review, we focus on cerebral (CDNF), an unconventional protein. CDNF delivered to brain parenchyma protects restores animal models recent Phase I-II trial was found safe well tolerated. deletion mice led age-dependent functional changes system loss enteric resulting slower gastrointestinal motility. These defects Cdnf-/- intriguingly resemble deficiencies observed early stage Different classical NTFs, can both extracellular trophic intracellular, endoplasmic reticulum (ER) luminal protein other types against ER stress. Similarly homologous mesencephalic astrocyte-derived (MANF), able stress-induced unfolded response (UPR) signaling homeostasis ER. Since stress thought be one pathophysiological mechanisms contributing degeneration PD, CDNF, its small-molecule derivatives under may provide useful tools experimental medicine future therapies protein-misfolding

Language: Английский

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Empagliflozin alleviates endoplasmic reticulum stress and augments autophagy in rotenone-induced Parkinson's disease in rats: Targeting the GRP78/PERK/eIF2α/CHOP pathway and miR-211-5p

Chemico-Biological Interactions, Journal Year: 2022, Volume and Issue: 362, P. 110002 - 110002

Published: May 30, 2022

Language: Английский

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The principal molecular mechanisms behind the activation of Keap1/Nrf2/ARE pathway leading to neuroprotective action in Parkinson's disease

Neurochemistry International, Journal Year: 2022, Volume and Issue: 156, P. 105325 - 105325

Published: March 9, 2022

Language: Английский

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The Common Cellular Events in the Neurodegenerative Diseases and the Associated Role of Endoplasmic Reticulum Stress

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 5894 - 5894

Published: May 24, 2022

Neurodegenerative diseases are inseparably linked with aging and increase as life expectancy extends. There common dysfunctions in various cellular events shared among neurogenerative diseases, such calcium dyshomeostasis, neuroinflammation, age-associated decline the autophagy-lysosome system. However, most of all, prominent pathological feature neurodegenerative is toxic buildup misfolded protein aggregates inclusion bodies accompanied by an impairment proteostasis. Recent studies have suggested a close association between endoplasmic reticulum (ER) stress pathology animal models well human patients. The contribution mutant or protein-triggered ER its associated signaling events, unfolded response (UPR), to pathophysiology disorders, including Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis, prion described here. Impaired UPR action commonly attributed exacerbated stress, pathogenic aggregate accumulation, deteriorating pathologies. Thus, activating certain components has been shown alleviate neurodegeneration. uncontrolled activation some factors also demonstrated worsen phenotypes, suggesting that detailed molecular mechanisms around related neurodegenerations should be understood develop effective therapeutics against aging-associated neurological syndromes. We discuss current therapeutic endeavors, development small molecules selectively target individual address general.

Language: Английский

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Association between theLRP1BandAPOEloci and the development of Parkinson’s disease dementia

Brain, Journal Year: 2022, Volume and Issue: 146(5), P. 1873 - 1887

Published: Nov. 9, 2022

Parkinson's disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features disease, particularly in later stages disease. However, rate decline varies among patients, genetic basis for this heterogeneity incompletely understood. To explore factors associated with progression to dementia, we performed genome-wide survival meta-analysis 3923 clinically diagnosed cases European ancestry from four longitudinal cohorts. In total, 6.7% individuals developed during study follow-up, on average 4.4 ± 2.4 years diagnosis. We have identified APOE ε4 allele as major risk factor conversion [hazard ratio = 2.41 (1.94-3.00), P 2.32 × 10-15], well new locus within ApoE APP receptor LRP1B gene 3.23 (2.17-4.81), 7.07 10-09]. candidate analysis, GBA variants were also be higher 2.02 (1.21-3.32), 0.007]. CSF biomarker analysis implicated amyloid pathway significantly reduced levels β42 (P 0.0012) compared without dementia. These results identify faster suggest that amyloid-targeting therapy may role preventing

Language: Английский

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