scholarly journals Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates

2020 ◽  
Vol 21 (9) ◽  
pp. 3369 ◽  
Author(s):  
Hyungsun Park ◽  
Ju-Hee Kang ◽  
Seongju Lee
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Inclusion Bodies ◽  
Amyloid Β ◽  
Control Mechanisms ◽  
Autophagy Induction ◽  
Ubiquitin Proteasome ◽  
Autophagy Pathway ◽  
The Relationship ◽  
Intracellular Inclusion

Cells have developed elaborate quality-control mechanisms for proteins and organelles to maintain cellular homeostasis. Such quality-control mechanisms are maintained by conformational folding via molecular chaperones and by degradation through the ubiquitin-proteasome or autophagy-lysosome system. Accumulating evidence suggests that impaired autophagy contributes to the accumulation of intracellular inclusion bodies consisting of misfolded proteins, which is a hallmark of most neurodegenerative diseases. In addition, genetic mutations in core autophagy-related genes have been reported to be linked to neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. Conversely, the pathogenic proteins, such as amyloid β and α-synuclein, are detrimental to the autophagy pathway. Here, we review the recent advances in understanding the relationship between autophagic defects and the pathogenesis of neurodegenerative diseases and suggest autophagy induction as a promising strategy for the treatment of these conditions.

Neurodegenerative Diseases as Protein Misfolding Disorders

2016 ◽  
Author(s):  
Tomohiro Nakamura ◽  
Stuart A. Lipton
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Protein Misfolding ◽  
Protein Quality ◽  
Protein S ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Redox Stress ◽  
Chemical Mechanisms ◽  
Ubiquitin Proteasome

Neurodegenerative diseases (NDDs) often represent disorders of protein folding. Rather than large aggregates, recent evidence suggests that soluble oligomers of misfolded proteins are the most neurotoxic species. Emerging evidence points to small, soluble oligomers of misfolded proteins as the cause of synaptic dysfunction and loss, the major pathological correlate to disease progression in many NDDs including Alzheimer’s disease. The protein quality control machinery of the cell, which includes molecular chaperones as found in the endoplasmic reticulum (ER), the ubiquitin-proteasome system (UPS), and various forms of autophagy, can counterbalance the accumulation of misfolded proteins to some extent. Their ability to eliminate the neurotoxic effects of misfolded proteins, however, declines with age. A plausible explanation for the age-dependent deterioration of the quality control machinery involves compromise of these systems by excessive generation of reactive oxygen species (ROS), such as superoxide anion (O2-), and reactive nitrogen species (RNS), such as nitric oxide (NO). The resulting redox stress contributes to the accumulation of misfolded proteins. Here, we focus on aberrantly increased generation of NO-related species since this process appears to accelerate the manifestation of key neuropathological features, including protein misfolding. We review the chemical mechanisms of posttranslational modification by RNS such as protein S-nitrosylation of critical cysteine thiol groups and nitration of tyrosine residues, showing how they contribute to the pathogenesis of NDDs.

scholarly journals Intersection between Redox Homeostasis and Autophagy: Valuable Insights into Neurodegeneration

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 694
Author(s):  
Hyungsun Park ◽  
Jongyoon Kim ◽  
Chihoon Shin ◽  
Seongju Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Redox Homeostasis ◽  
Degradation Pathway ◽  
Pharmacological Intervention ◽  
Oxygen Species ◽  
Promising Strategy ◽  
Autophagy Induction ◽  
The Relationship ◽  
The Brain ◽  
Lateral Sclerosis

Autophagy, a main degradation pathway for maintaining cellular homeostasis, and redox homeostasis have recently been considered to play protective roles in neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Increased levels of reactive oxygen species (ROS) in neurons can induce mitochondrial damage and protein aggregation, thereby resulting in neurodegeneration. Oxidative stress is one of the major activation signals for the induction of autophagy. Upon activation, autophagy can remove ROS, damaged mitochondria, and aggregated proteins from the cells. Thus, autophagy can be an effective strategy to maintain redox homeostasis in the brain. However, the interaction between redox homeostasis and autophagy is not clearly elucidated. In this review, we discuss recent studies on the relationship between redox homeostasis and autophagy associated with neurodegenerative diseases and propose that autophagy induction through pharmacological intervention or genetic activation might be a promising strategy to treat these disorders.

scholarly journals Protein and Mitochondria Quality Control Mechanisms and Cardiac Aging

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 933 ◽  
Author(s):  
Rajeshwary Ghosh ◽  
Vishaka Vinod ◽  
J. David Symons ◽  
Sihem Boudina
Keyword(s):  
Quality Control ◽  
Myocardial Dysfunction ◽  
Indirect Costs ◽  
The United States ◽  
Cardiovascular Complications ◽  
Control Mechanisms ◽  
Cardiac Aging ◽  
The Us ◽  
Ubiquitin Proteasome ◽  
Primary Risk Factor

Cardiovascular disease (CVD) is the number one cause of death in the United States. Advancing age is a primary risk factor for developing CVD. Estimates indicate that 20% of the US population will be ≥65 years old by 2030. Direct expenditures for treating CVD in the older population combined with indirect costs, secondary to lost wages, are predicted to reach $1.1 trillion by 2035. Therefore, there is an eminent need to discover novel therapeutic targets and identify new interventions to delay, lessen the severity, or prevent cardiovascular complications associated with advanced age. Protein and organelle quality control pathways including autophagy/lysosomal and the ubiquitin-proteasome systems, are emerging contributors of age-associated myocardial dysfunction. In general, two findings have sparked this interest. First, strong evidence indicates that cardiac protein degradation pathways are altered in the heart with aging. Second, it is well accepted that damaged and misfolded protein aggregates and dysfunctional mitochondria accumulate in the heart with age. In this review, we will: (i) define the different protein and mitochondria quality control mechanisms in the heart; (ii) provide evidence that each quality control pathway becomes dysfunctional during cardiac aging; and (iii) discuss current advances in targeting these pathways to maintain cardiac function with age.

scholarly journals Threshold concentration and random collision determine the growth of the phase-separated huntingtin inclusion from a stable core

2020 ◽  
Author(s):  
Sen Pei ◽  
Theresa C. Swayne ◽  
Jeffrey F. Morris ◽  
Lesley Emtage
Keyword(s):  
Growth Rate ◽  
Confocal Microscopy ◽  
Neurodegenerative Diseases ◽  
Inclusion Bodies ◽  
Threshold Concentration ◽  
Mutant Huntingtin ◽  
Unfolded Protein ◽  
Stable Core ◽  
The Relationship

AbstractThe processes underlying formation and growth of unfolded protein inclusions are relevant to neurodegenerative diseases. In S. cerevisiae, inclusion bodies formed by mutant huntingtin have characteristics of phase-separated compartments: they are mobile, ovoid, and the contents are diffusible. We have used molecular genetics and quantitative confocal microscopy to probe the relationship between concentration and inclusion growth in vivo. Our analysis and modeling of the growth of mutant huntingtin inclusion bodies (mHtt IBs) suggests that there is a cytoplasmic threshold concentration that triggers the formation of an IB, regardless of proteasome capacity, and that reduction in cytoplasmic mHtt causes IBs to shrink. These findings confirm that the IB is a phase-separated compartment that continuously exchanges material with the cytoplasm. The growth rate of the IB is most consistent with a model in which material is incorporated through collision with the IB. A small remnant of the IB is relatively long-lasting, suggesting that the IB contains a core that is structurally distinct, and which may serve to nucleate it.

scholarly journals Peroxisome quality control and dysregulated lipid metabolism in neurodegenerative diseases

2020 ◽  
Vol 52 (9) ◽  
pp. 1486-1495
Author(s):  
Doo Sin Jo ◽  
Na Yeon Park ◽  
Dong-Hyung Cho
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Control Systems ◽  
Recent Progress ◽  
Current Evidence ◽  
Control Mechanisms ◽  
Peroxisome Biogenesis ◽  
Peroxisomal Function ◽  
Cellular Organelles

Abstract In recent decades, the role of the peroxisome in physiology and disease conditions has become increasingly important. Together with the mitochondria and other cellular organelles, peroxisomes support key metabolic platforms for the oxidation of various fatty acids and regulate redox conditions. In addition, peroxisomes contribute to the biosynthesis of essential lipid molecules, such as bile acid, cholesterol, docosahexaenoic acid, and plasmalogen. Therefore, the quality control mechanisms that regulate peroxisome biogenesis and degradation are important for cellular homeostasis. Current evidence indicates that peroxisomal function is often reduced or dysregulated in various human disease conditions, such as neurodegenerative diseases. Here, we review the recent progress that has been made toward understanding the quality control systems that regulate peroxisomes and their pathological implications.

scholarly journals Saturated Proteostasis and Nuclear Injuries Defeat Homeostatic Potentials of α-Synuclein Filaments

2021 ◽  
Author(s):  
Shemin Mansuri ◽  
Richa Singh ◽  
Shivali Rawat ◽  
Aanchal Jain ◽  
Debodyuti Mondal ◽  
...  
Keyword(s):  
Quality Control ◽  
Nuclear Envelope ◽  
Protein Degradation ◽  
Inclusion Bodies ◽  
Protein Quality ◽  
The Other ◽  
Cellular Functions ◽  
Dual Purpose ◽  
Ubiquitin Proteasome ◽  
Filamentous Inclusions

Biogenesis of inclusion bodies (IBs) contributes to protein quality control (PQC). Perinuclear IBs like aggresomes/JUNQs serve as sites for ubiquitin-proteasome mediated protein degradation. The other canonical IB, IPOD, does not degrade but sequesters non-ubiquitinated terminally aggregated proteins to prevent their promiscuous interactions and interferences with other cellular functions. Here, we show that as a deviation from this convention, misfolding-prone α-Synuclein is simultaneously deposited into two distinct IBs - Syn-aggresomes and seeding based filamentous inclusions (Syn-filaments), both acting as sites for ubiquitin-proteasome mediated protein degradation. Syn-aggresomes buffer the spontaneous turnover of α-Synuclein. Syn-filaments serve the dual purpose of self-sequestration and opportunistic degradation. Counterintuitively, overgrowth of perinuclear Syn-filaments titrates out cellular PQC-pool and challenges the turnover and solubility of other misfolding-prone proteins. Moreover, large Syn-filaments associate with LaminB1, mount mechanical stress on nuclear envelope via dynein, disrupt nuclear integrity, and deregulate stress-triggered transcription of chaperones failing their homeostatic potential.

scholarly journals Mitochondrial Quality Control in the Maintenance of Cardiovascular Homeostasis: The Roles and Interregulation of UPS, Mitochondrial Dynamics and Mitophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Yujie Song ◽  
Yuerong Xu ◽  
Yingying Liu ◽  
Jie Gao ◽  
Lele Feng ◽  
...  
Keyword(s):  
Quality Control ◽  
Mitochondrial Dynamics ◽  
Ubiquitin Proteasome System ◽  
Normal Function ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Dynamic ◽  
Profound Influence ◽  
Ubiquitin Proteasome ◽  
And Function ◽  
The Relationship

Maintenance of normal function of mitochondria is vital to the fate and health of cardiomyocytes. Mitochondrial quality control (MQC) mechanisms are essential in governing mitochondrial integrity and function. The ubiquitin-proteasome system (UPS), mitochondrial dynamics, and mitophagy are three major components of MQC. With the progress of research, our understanding of MQC mechanisms continues to deepen. Gradually, we realize that the three MQC mechanisms are not independent of each other. To the contrary, there are crosstalk among the mechanisms, which can make them interact with each other and cooperate well, forming a triangle interplay. Briefly, the UPS system can regulate the level of mitochondrial dynamic proteins and mitophagy receptors. In the process of Parkin-dependent mitophagy, the UPS is also widely activated, performing critical roles. Mitochondrial dynamics have a profound influence on mitophagy. In this review, we provide new processes of the three major MQC mechanisms in the background of cardiomyocytes and delve into the relationship between them.

scholarly journals Mitochondrial Quality Control Strategies: Potential Therapeutic Targets for Neurodegenerative Diseases?

2021 ◽  
Vol 15 ◽  
Author(s):  
Di Hu ◽  
Zunren Liu ◽  
Xin Qi
Keyword(s):  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Therapeutic Potential ◽  
Mitochondrial Dynamics ◽  
Control Strategies ◽  
Atp Synthesis ◽  
Great Promise ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Integrity

Many lines of evidence have indicated the therapeutic potential of rescuing mitochondrial integrity by targeting specific mitochondrial quality control pathways in neurodegenerative diseases, such as Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease. In addition to ATP synthesis, mitochondria are critical regulators of ROS production, lipid metabolism, calcium buffering, and cell death. The mitochondrial unfolded protein response, mitochondrial dynamics, and mitophagy are the three main quality control mechanisms responsible for maintaining mitochondrial proteostasis and bioenergetics. The proper functioning of these complex processes is necessary to surveil and restore mitochondrial homeostasis and the healthy pool of mitochondria in cells. Mitochondrial dysfunction occurs early and causally in disease pathogenesis. A significant accumulation of mitochondrial damage resulting from compromised quality control pathways leads to the development of neuropathology. Moreover, genetic or pharmaceutical manipulation targeting the mitochondrial quality control mechanisms can sufficiently rescue mitochondrial integrity and ameliorate disease progression. Thus, therapies that can improve mitochondrial quality control have great promise for the treatment of neurodegenerative diseases. In this review, we summarize recent progress in the field that underscores the essential role of impaired mitochondrial quality control pathways in the pathogenesis of neurodegenerative diseases. We also discuss the translational approaches targeting mitochondrial function, with a focus on the restoration of mitochondrial integrity, including mitochondrial dynamics, mitophagy, and mitochondrial proteostasis.

scholarly journals Heat Shock Proteins: Cell Protection through Protein Triage

2010 ◽  
Vol 10 ◽  
pp. 1543-1552 ◽  
Author(s):  
David Lanneau ◽  
Guillaume Wettstein ◽  
Philippe Bonniaud ◽  
Carmen Garrido
Keyword(s):  
Quality Control ◽  
Heat Shock ◽  
Heat Shock Proteins ◽  
Protein Quality ◽  
Ubiquitin Proteasome System ◽  
Control Mechanisms ◽  
Cell Protection ◽  
Ubiquitin Proteasome ◽  
Folded Proteins ◽  
Shock Proteins

Heat shock proteins (HSPs) are chaperones that catalyze the proper folding of nascent proteins and the refolding of denatured proteins. The ubiquitin-proteasome system is an error-checking system that directs improperly folded proteins for destruction. A coordinated interaction between the HSPs (renaturation) and the proteasome (degradation) must exist to assure protein quality control mechanisms. Although it still remains unknown how the decision of folding vs. degradation is taken, many pieces of evidence demonstrate that HSPs interact directly or indirectly with the proteasome, assuring quite selectively the proteasomal degradation of certain proteins under stress conditions. In this review, we will describe the different data that demonstrate a role for HSP90, HSP70, HSP27, and alpha-B-crystallin in the partitioning of proteins to either one of these pathways, referred as protein triage.

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