scholarly journals Crosstalk between Endoplasmic Reticulum Stress and Protein Misfolding in Neurodegenerative Diseases

2013 ◽  
Vol 2013 ◽  
pp. 1-22 ◽  
Author(s):  
Cláudia M. F. Pereira
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Prion Diseases ◽  
Protein Quality Control ◽  
Subcellular Compartment ◽  
Novel Therapeutic Strategies

Under physiological conditions, the endoplasmic reticulum (ER) is a central subcellular compartment for protein quality control in the secretory pathway that prevents protein misfolding and aggregation. Instrumental in protein quality control in the ER is the unfolded protein response (UPR), which is activated upon ER stress to reestablish homeostasis through a sophisticated transcriptionally and translationally regulated signaling network. However, this response can lead to apoptosis if the stress cannot be alleviated. The presence of abnormal protein aggregates containing specific misfolded proteins is recognized as the basis of numerous human conformational disorders, including neurodegenerative diseases. Here, I will highlight the overwhelming evidence that the presence of specific aberrant proteins in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), prion diseases, and Amyotrophic Lateral Sclerosis (ALS) is intimately associated with perturbations in the ER protein quality control machinery that become incompetent to restore protein homeostasis and shift adaptive programs toward the induction of apoptotic signaling to eliminate irreversibly damaged neurons. Increasing our understanding about the deadly crosstalk between ER dysfunction and protein misfolding in these neurodegenerative diseases may stimulate the development of novel therapeutic strategies able to support neuronal survival and ameliorate disease progression.

scholarly journals Ubiquitin and Parkinson's disease through the looking glass of genetics

2017 ◽  
Vol 474 (9) ◽  
pp. 1439-1451 ◽  
Author(s):  
Helen Walden ◽  
Miratul M.K. Muqit
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Neuronal Loss ◽  
Protein Quality Control ◽  
Biochemical Alterations ◽  
Ubiquitin System ◽  
Novel Therapeutic Strategies

Biochemical alterations found in the brains of Parkinson's disease (PD) patients indicate that cellular stress is a major driver of dopaminergic neuronal loss. Oxidative stress, mitochondrial dysfunction, and ER stress lead to impairment of the homeostatic regulation of protein quality control pathways with a consequent increase in protein misfolding and aggregation and failure of the protein degradation machinery. Ubiquitin signalling plays a central role in protein quality control; however, prior to genetic advances, the detailed mechanisms of how impairment in the ubiquitin system was linked to PD remained mysterious. The discovery of mutations in the α-synuclein gene, which encodes the main protein misfolded in PD aggregates, together with mutations in genes encoding ubiquitin regulatory molecules, including PTEN-induced kinase 1 (PINK1), Parkin, and FBX07, has provided an opportunity to dissect out the molecular basis of ubiquitin signalling disruption in PD, and this knowledge will be critical for developing novel therapeutic strategies in PD that target the ubiquitin system.

Protein quality control at the endoplasmic reticulum

2016 ◽  
Vol 60 (2) ◽  
pp. 227-235 ◽  
Author(s):  
Kathleen McCaffrey ◽  
Ineke Braakman
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Secretory Pathway ◽  
Protein Quality ◽  
Bond Formation ◽  
Protein Quality Control ◽  
Secretory Proteins ◽  
Protein Quality Control System ◽  
And Function ◽  
Extracellular Environment

The ER (endoplasmic reticulum) is the protein folding ‘factory’ of the secretory pathway. Virtually all proteins destined for the plasma membrane, the extracellular space or other secretory compartments undergo folding and maturation within the ER. The ER hosts a unique PQC (protein quality control) system that allows specialized modifications such as glycosylation and disulfide bond formation essential for the correct folding and function of many secretory proteins. It is also the major checkpoint for misfolded or aggregation-prone proteins that may be toxic to the cell or extracellular environment. A failure of this system, due to aging or other factors, has therefore been implicated in a number of serious human diseases. In this article, we discuss several key features of ER PQC that maintain the health of the cellular secretome.

Evidence Linking Protein Misfolding to Quality Control in Progressive Neurodegenerative Diseases

2020 ◽  
Vol 20 (23) ◽  
pp. 2025-2043 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Md. Sahab Uddin ◽  
Ahmed Abdeen ◽  
Ghulam Md Ashraf ◽  
Asma Perveen ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Protein Quality ◽  
Prion Diseases ◽  
Cellular Protein ◽  
Sequence Motif ◽  
Native Proteins ◽  
Usual Process

Several proteolytic systems including ubiquitin (Ub)-proteasome system (UPS), chaperonemediated autophagy (CMA), and macroautophagy are used by the mammalian cells to remove misfolded proteins (MPs). UPS mediates degradation of most of the MPs, where Ub-conjugated substrates are deubiquitinated, unfolded, and passed through the proteasome’s narrow chamber, and eventually break into smaller peptides. It has been observed that the substrates that show a specific degradation signal, the KFERQ sequence motif, can be delivered to and go through CMA-mediated degradation in lysosomes. Macroautophagy can help in the degradation of substrates that are prone to aggregation and resistant to both the CMA and UPS. In the aforesaid case, cargoes are separated into autophagosomes before lysosomal hydrolase-mediated degradation. Even though the majority of the aggregated and MPs in the human proteome can be removed via cellular protein quality control (PQC), some mutant and native proteins tend to aggregate into β-sheet-rich oligomers that exhibit resistance to all identified proteolytic processes and can, therefore, grow into extracellular plaques or inclusion bodies. Indeed, the buildup of protease-resistant aggregated and MPs is a usual process underlying various protein misfolding disorders, including neurodegenerative diseases (NDs) for example Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and prion diseases. In this article, we have focused on the contribution of PQC in the degradation of pathogenic proteins in NDs.

scholarly journals USP7 regulates ALS-associated proteotoxicity and quality control through the NEDD4L–SMAD pathway

2020 ◽  
Vol 117 (45) ◽  
pp. 28114-28125
Author(s):  
Tao Zhang ◽  
Goran Periz ◽  
Yu-Ning Lu ◽  
Jiou Wang
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Mammalian Cells ◽  
Transforming Growth Factor ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Transforming Growth Factor Β ◽  
Misfolded Proteins ◽  
A Genome

An imbalance in cellular homeostasis occurring as a result of protein misfolding and aggregation contributes to the pathogeneses of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we report the identification of a ubiquitin-specific protease, USP7, as a regulatory switch in a protein quality-control system that defends against proteotoxicity. A genome-wide screen in aCaenorhabditis elegansmodel of SOD1-linked ALS identified the USP7 ortholog as a suppressor of proteotoxicity in the nervous system. The actions of USP7 orthologs on misfolded proteins were found to be conserved inDrosophilaand mammalian cells. USP7 acts on protein quality control through the SMAD2 transcription modulator of the transforming growth factor β pathway, which activates autophagy and enhances the clearance of misfolded proteins. USP7 deubiquitinates the E3 ubiquitin ligase NEDD4L, which mediates the degradation of SMAD2. Inhibition of USP7 protected against proteotoxicity in mammalian neurons, and SMAD2 was found to be dysregulated in the nervous systems of ALS patients. These findings reveal a regulatory pathway of protein quality control that is implicated in the proteotoxicity-associated neurodegenerative diseases.

The endoplasmic reticulum: A hub of protein quality control in health and disease

2017 ◽  
Vol 108 ◽  
pp. 383-393 ◽  
Author(s):  
Lisa Vincenz-Donnelly ◽  
Mark S. Hipp
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Health And Disease

Endoplasmic Reticulum Protein Quality Control and Degradation

2008 ◽  
pp. 123-143
Author(s):  
Antje Schfer ◽  
Zlatka Kostova ◽  
Dieter H. Wolf
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Endoplasmic Reticulum Protein

scholarly journals Protein quality control through endoplasmic reticulum-associated degradation maintains haematopoietic stem cell identity and niche interactions

2020 ◽  
Vol 22 (10) ◽  
pp. 1162-1169 ◽  
Author(s):  
Longyong Xu ◽  
Xia Liu ◽  
Fanglue Peng ◽  
Weijie Zhang ◽  
Liting Zheng ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Stem Cell ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Haematopoietic Stem Cell ◽  
Cell Identity ◽  
Endoplasmic Reticulum Associated Degradation

scholarly journals Characterization of an ERAD Gene as VPS30/ATG6 Reveals Two Alternative and Functionally Distinct Protein Quality Control Pathways: One for Soluble Z Variant of Human α-1 Proteinase Inhibitor (A1PiZ) and Another for Aggregates of A1PiZ

2006 ◽  
Vol 17 (1) ◽  
pp. 203-212 ◽  
Author(s):  
Kristina B. Kruse ◽  
Jeffrey L. Brodsky ◽  
Ardythe A. McCracken
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Proteinase Inhibitor ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Carboxypeptidase Y ◽  
Complex Nature ◽  
Secretion Pathway ◽  
Golgi Network ◽  
Yeast Mutants

The Z variant of human α-1 proteinase inhibitor (A1PiZ) is a substrate for endoplasmic reticulum-associated protein degradation (ERAD). To identify genes required for the degradation of this protein, A1PiZ degradation-deficient (add) yeast mutants were isolated. The defect in one of these mutants, add3, was complemented by VPS30/ATG6, a gene that encodes a component of two phosphatidylinositol 3-kinase (PtdIns 3-kinase) complexes: complex I is required for autophagy, whereas complex II is required for the carboxypeptidase Y (CPY)-to-vacuole pathway. We found that upon overexpression of A1PiZ, both PtdIns 3-kinase complexes were required for delivery of the excess A1PiZ to the vacuole. When the CPY-to-vacuole pathway was compromised, A1PiZ was secreted; however, disruption of autophagy led to an increase in aggregated A1PiZ rather than secretion. These results suggest that excess soluble A1PiZ transits the secretion pathway to the trans-Golgi network and is selectively targeted to the vacuole via the CPY-to-vacuole sorting pathway, but excess A1PiZ that forms aggregates in the endoplasmic reticulum is targeted to the vacuole via autophagy. These findings illustrate the complex nature of protein quality control in the secretion pathway and reveal multiple sites that recognize and sort both soluble and aggregated forms of aberrant or misfolded proteins.

scholarly journals Protein Domains Involved in Assembly in the Endoplasmic Reticulum Promote Vacuolar Delivery when Fused to Secretory GFP, Indicating a Protein Quality Control Pathway for Degradation in the Plant Vacuole

2008 ◽  
Vol 1 (6) ◽  
pp. 1067-1076 ◽  
Author(s):  
Ombretta Foresti ◽  
Francesca De Marchis ◽  
Maddalena de Virgilio ◽  
Eva M. Klein ◽  
Sergio Arcioni ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Protein Quality ◽  
Protein Domains ◽  
Protein Quality Control ◽  
Plant Vacuole
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