scholarly journals Proteostasis and Mitochondrial Role on Psychiatric and Neurodegenerative Disorders: Current Perspectives

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Pablo Olivero ◽  
Carlo Lozano ◽  
Ramón Sotomayor-Zárate ◽  
Nicolás Meza-Concha ◽  
Marcelo Arancibia ◽  
...  
Keyword(s):  
Neurodegenerative Disorders ◽  
Protein Misfolding ◽  
Cell Damage ◽  
Mitochondrial Dynamics ◽  
Ubiquitin Proteasome System ◽  
Compensatory Mechanisms ◽  
Mitochondrial Functions ◽  
Ubiquitin Proteasome ◽  
Psychiatric Conditions ◽  
Therapeutic Alternatives

Proteostasis involves processes that are fundamental for neural viability. Thus, protein misfolding and the formation of toxic aggregates at neural level, secondary to dysregulation of the conservative mechanisms of proteostasis, are associated with several neuropsychiatric conditions. It has been observed that impaired mitochondrial function due to a dysregulated proteostasis control system, that is, ubiquitin-proteasome system and chaperones, could also have effects on neurodegenerative disorders. We aimed to critically analyze the available findings regarding the neurobiological implications of proteostasis on the development of neurodegenerative and psychiatric diseases, considering the mitochondrial role. Proteostasis alterations in the prefrontal cortex implicate proteome instability and accumulation of misfolded proteins. Altered mitochondrial dynamics, especially in proteostasis processes, could impede the normal compensatory mechanisms against cell damage. Thereby, altered mitochondrial functions on regulatory modulation of dendritic development, neuroinflammation, and respiratory function may underlie the development of some psychiatric conditions, such as schizophrenia, being influenced by a genetic background. It is expected that with the increasing evidence about proteostasis in neuropsychiatric disorders, new therapeutic alternatives will emerge.

Protein Quality Control in Neurodegeneration and Neuroprotection

2020 ◽  
pp. 1-24
Author(s):  
Yasmeena Akhter ◽  
Jahangir Nabi ◽  
Hinna Hamid ◽  
Nahida Tabassum ◽  
Faheem Hyder Pottoo ◽  
...  
Keyword(s):  
Quality Control ◽  
Neurodegenerative Disorders ◽  
Protein Quality ◽  
Protein Quality Control ◽  
Ubiquitin Proteasome System ◽  
Security System ◽  
Conformational Disorders ◽  
Ubiquitin Proteasome ◽  
Multi Level

Proteostasis is essential for regulating the integrity of the proteome. Disruption of proteostasis under some rigorous conditions leads to the aggregation and accumulation of misfolded toxic proteins, which plays a central role in the pathogenesis of protein conformational disorders. The protein quality control (PQC) system serves as a multi-level security system to shield cells from abnormal proteins. The intrinsic PQC systems maintaining proteostasis include the ubiquitin-proteasome system (UPS), chaperon-mediated autophagy (CMA), and autophagy-lysosome pathway (ALP) that serve to target misfolded proteins for unfolding, refolding, or degradation. Alterations of PQC systems in neurons have been implicated in the pathogenesis of various neurodegenerative disorders. This chapter provides an overview of PQC pathways to set a framework for discussion of the role of PQC in neurodegenerative disorders. Additionally, various pharmacological approaches targeting PQC are summarized.

scholarly journals The ubiquitin proteasome system in synaptic and axonal degeneration

2004 ◽  
Vol 165 (1) ◽  
pp. 27-30 ◽  
Author(s):  
Laura Korhonen ◽  
Dan Lindholm
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disorders ◽  
Drug Targets ◽  
Axonal Degeneration ◽  
Fruit Fly ◽  
Ubiquitin Proteasome System ◽  
Synaptic Protein ◽  
Ubiquitin Proteasome ◽  
Novel Drug ◽  
Novel Drug Targets

The ubiquitin proteasome system (UPS) contributes to the pathophysiology of neurodegenerative diseases, and it is also a major determinant of synaptic protein degradation and activity. Recent studies in rodents and in the fruit fly Drosophila have shown that the activity of the UPS is involved in axonal degeneration. Increased knowledge of the UPS in synaptic and axonal reactions may provide novel drug targets for treatments of neuronal injuries and neurodegenerative disorders.

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.

The ubiquitin–proteasome system regulates the stability and activity of the glucose sensor glucokinase in pancreatic β-cells

2013 ◽  
Vol 456 (2) ◽  
pp. 173-184 ◽  
Author(s):  
Anke Hofmeister-Brix ◽  
Sigurd Lenzen ◽  
Simone Baltrusch
Keyword(s):  
Protein Misfolding ◽  
Glucose Sensor ◽  
Ubiquitin Proteasome System ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
Insulin Secreting Cells ◽  
Ubiquitin Proteasome ◽  
The Stability

The glucose phosphorylating enzyme glucokinase is regulated by the ubiquitin–proteasome system. Inhibition of the proteasome leads to reduced glucokinase activity, glucokinase protein misfolding and localization of glucokinase in aggresomes in insulin-secreting cells, pancreatic β-cells and hepatocytes.

scholarly journals Mitochondrial dysfunction and neurodegenerative proteinopathies: mechanisms and prospects for therapeutic intervention

2018 ◽  
Vol 46 (4) ◽  
pp. 829-842 ◽  
Author(s):  
Thomas Briston ◽  
Amy R. Hicks
Keyword(s):  
Mitochondrial Dynamics ◽  
Ubiquitin Proteasome System ◽  
Misfolded Proteins ◽  
Metabolic Dysfunction ◽  
Loss Of Function ◽  
Deubiquitinating Enzymes ◽  
Cell Death Pathways ◽  
Intervention Point ◽  
Ubiquitin Proteasome ◽  
Atp Supply

Neurodegenerative proteinopathies are a group of pathologically similar, progressive disorders of the nervous system, characterised by structural alterations within and toxic misfolding of susceptible proteins. Oligomerisation of Aβ, tau, α-synuclein and TDP-43 leads to a toxin gain- or loss-of-function contributing to the phenotype observed in Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and frontotemporal dementia. Misfolded proteins can adversely affect mitochondria, and post-mitotic neurones are especially sensitive to metabolic dysfunction. Misfolded proteins impair mitochondrial dynamics (morphology and trafficking), preventing functional mitochondria reaching the synapse, the primary site of ATP utilisation. Furthermore, a direct association of misfolded proteins with mitochondria may precipitate or augment dysfunctional oxidative phosphorylation and mitochondrial quality control, causing redox dyshomeostasis observed in disease. As such, a significant interest lies in understanding mechanisms of mitochondrial toxicity in neurodegenerative disorders and in dissecting these mechanisms with a view of maintaining mitochondrial homeostasis in disease. Recent advances in understanding mitochondrially controlled cell death pathways and elucidating the mitochondrial permeability pore bioarchitecture are beginning to present new avenues to target neurodegeneration. Novel mitochondrial roles of deubiquitinating enzymes are coming to light and present an opportunity for a new class of proteins to target therapeutically with the aim of promoting mitophagy and the ubiquitin–proteasome system. The brain is enormously metabolically active, placing a large emphasis on maintaining ATP supply. Therefore, identifying mechanisms to sustain mitochondrial function may represent a common intervention point across all proteinopathies.

scholarly journals Canonical and non-canonical autophagy pathways in microglia

2020 ◽  
Author(s):  
Julia Jülg ◽  
Laura Strohm ◽  
Christian Behrends
Keyword(s):  
Neurodegenerative Disorders ◽  
Current Knowledge ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Brain Health ◽  
The Past ◽  
Long Time ◽  
Ubiquitin Proteasome ◽  
Autophagy Activity

Besides the ubiquitin-proteasome-system, autophagy is a major degradation pathway within cells. It delivers invading pathogens, damaged organelles, aggregated proteins and other macromolecules from the cytosol to the lysosome for bulk degradation. This so-called canonical autophagy activity contributes to the maintenance of organelle, protein and metabolite homeostasis as well as innate immunity. Over the past years, numerous studies rapidly deepened our knowledge on the autophagy machinery and its regulation; driven by the fact that impairment of autophagy is associated with several human pathologies including cancer, immune diseases and neurodegenerative disorders. Unexpectedly, components of the autophagic machinery were also found to participate in various processes that did not involve lysosomal delivery of cytosolic constituents. These functions are hereafter defined as non-canonical autophagy. Regarding neurodegenerative diseases, most research was performed in neurons, while for a long-time microglia received considerably less attention. Concomitant with the notion that microglia greatly contribute to brain health, the understanding of the role of autophagy in microglia expanded. To facilitate an overview of the current knowledge, we present herein the fundamentals as well as the recent advances of canonical and non-canonical autophagy functions in microglia.

scholarly journals The Autophagy-Lysosomal Pathways and Their Emerging Roles in Modulating Proteostasis in Tumors

Cells ◽  
2018 ◽  
Vol 8 (1) ◽  
pp. 4 ◽  
Author(s):  
Zhen Dong ◽  
Hongjuan Cui
Keyword(s):  
Protein Misfolding ◽  
Tumor Development ◽  
Ubiquitin Proteasome System ◽  
Tumor Treatment ◽  
Unfolded Protein ◽  
Normal Physiological Condition ◽  
Ubiquitin Proteasome ◽  
The Alps ◽  
Protein Response ◽  
Chaperone Mediated Autophagy

In normal physiological condition, the maintenance of cellular proteostasis is a prerequisite for cell growth, functioning, adapting to changing micro-environments, and responding to extracellular stress. Cellular proteostasis is maintained by specific proteostasis networks (PNs) to prevent protein misfolding, aggregating, and accumulating in subcellular compartments. Commonly, the PNs are composed of protein synthesis, molecular chaperones, endoplasmic reticulum (ER), unfolded protein response (UPR), stress response pathways (SRPs), secretions, ubiquitin proteasome system (UPS), and autophagy-lysosomal pathways (ALPs). Although great efforts have been made to explore the underlying detailed mechanisms of proteostasis, there are many questions remain to explore, especially in proteostasis regulated by the ALPs. Proteostasis out-off-balance is correlated with various human diseases such as diabetes, stroke, inflammation, hypertension, pulmonary fibrosis, and Alzheimer’s disease. , enhanced regulation of PNs is observed in tumors, thereby indicating that proteostasis may play a pivotal role in tumorigenesis and cancer development. Recently, inhibitors targeting the UPS have shown to be failed in solid tumor treatment. However, there is growing evidence showing that the ALPs play important roles in regulation of proteostasis alone or with a crosstalk with other PNs in tumors. In this review, we provide insights into the proteostatic process and how it is regulated by the ALPs, such as macroautophagy, aggrephagy, chaperone-mediated autophagy, microautophagy, as well as mitophagy during tumor development.

scholarly journals Dysregulation of the Autophagy-Endolysosomal System in Amyotrophic Lateral Sclerosis and Related Motor Neuron Diseases

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Asako Otomo ◽  
Lei Pan ◽  
Shinji Hadano
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Protein Misfolding ◽  
Disease Onset ◽  
Ubiquitin Proteasome System ◽  
Protective Role ◽  
Motor Neuron Diseases ◽  
Ubiquitin Proteasome ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous group of incurable motor neuron diseases (MNDs) characterized by a selective loss of upper and lower motor neurons in the brain and spinal cord. Most cases of ALS are sporadic, while approximately 5–10% cases are familial. More than 16 causative genes for ALS/MNDs have been identified and their underlying pathogenesis, including oxidative stress, endoplasmic reticulum stress, excitotoxicity, mitochondrial dysfunction, neural inflammation, protein misfolding and accumulation, dysfunctional intracellular trafficking, abnormal RNA processing, and noncell-autonomous damage, has begun to emerge. It is currently believed that a complex interplay of multiple toxicity pathways is implicated in disease onset and progression. Among such mechanisms, ones that are associated with disturbances of protein homeostasis, the ubiquitin-proteasome system and autophagy, have recently been highlighted. Although it remains to be determined whether disease-associated protein aggregates have a toxic or protective role in the pathogenesis, the formation of them results from the imbalance between generation and degradation of misfolded proteins within neuronal cells. In this paper, we focus on the autophagy-lysosomal and endocytic degradation systems and implication of their dysfunction to the pathogenesis of ALS/MNDs. The autophagy-endolysosomal pathway could be a major target for the development of therapeutic agents for ALS/MNDs.

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