Degradation of tau protein by autophagy and proteasomal pathways

2012 ◽  
Vol 40 (4) ◽  
pp. 644-652 ◽  
Author(s):  
Yipeng Wang ◽  
Eckhard Mandelkow
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Degradation ◽  
Tau Protein ◽  
Therapeutic Strategy ◽  
Ubiquitin Proteasome System ◽  
Memory Deficit ◽  
Ubiquitin Proteasome ◽  
Ad Alzheimer’S Disease ◽  
Tau Aggregation ◽  
Stimulation Of

Tau aggregates are present in several neurodegenerative diseases and correlate with the severity of memory deficit in AD (Alzheimer's disease). However, the triggers of tau aggregation and tau-induced neurodegeneration are still elusive. The impairment of protein-degradation systems might play a role in such processes, as these pathways normally keep tau levels at a low level which may prevent aggregation. Some proteases can process tau and thus contribute to tau aggregation by generating amyloidogenic fragments, but the complete clearance of tau mainly relies on the UPS (ubiquitin–proteasome system) and the ALS (autophagy–lysosome system). In the present paper, we focus on the regulation of the degradation of tau by the UPS and ALS and its relation to tau aggregation. We anticipate that stimulation of these two protein-degradation systems might be a potential therapeutic strategy for AD and other tauopathies.

scholarly journals Methods to Discover and Evaluate Proteasome Small Molecule Stimulators

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2341 ◽  
Author(s):  
Rachel A. Coleman ◽  
Darci J. Trader
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Degradation ◽  
Small Molecule ◽  
Protease Activity ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Protein Accumulation ◽  
Toxic Protein ◽  
Disease States ◽  
Ubiquitin Proteasome

Protein accumulation has been identified as a characteristic of many degenerative conditions, such as neurodegenerative diseases and aging. In most cases, these conditions also present with diminished protein degradation. The ubiquitin-proteasome system (UPS) is responsible for the degradation of the majority of proteins in cells; however, the activity of the proteasome is reduced in these disease states, contributing to the accumulation of toxic protein. It has been hypothesized that proteasome activity, both ubiquitin-dependent and -independent, can be chemically stimulated to reduce the load of protein in diseased cells. Several methods exist to identify and characterize stimulators of proteasome activity. In this review, we detail the ways in which protease activity can be enhanced and analyze the biochemical and cellular methods of identifying stimulators of both the ubiquitin-dependent and -independent proteasome activities.

scholarly journals Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases

Life ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 607
Author(s):  
Soonsil Hyun ◽  
Dongyun Shin
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Degradation ◽  
Drug Targets ◽  
Ubiquitin Proteasome System ◽  
Cellular Protein ◽  
Therapeutic Modality ◽  
Target Proteins ◽  
Bifunctional Molecules ◽  
Ubiquitin Proteasome ◽  
Related Proteins

Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin–proteasome system and autophagy–lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases.

Ubiquitin-Dependent Proteolysis in Neurons

Physiology ◽  
2003 ◽  
Vol 18 (1) ◽  
pp. 29-33 ◽  
Author(s):  
Lars Klimaschewski
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Degradation ◽  
Current Knowledge ◽  
Neurological Diseases ◽  
Ubiquitin Proteasome System ◽  
Degradation Pathway ◽  
Present Review ◽  
Major Protein ◽  
Ubiquitin Proteasome ◽  
The Brain

Various studies identified the ubiquitin-proteasome system as the prime suspect in causing neurodegenerative diseases. The present review summarizes our current knowledge about the expression, regulation, and functions of this major protein degradation pathway in the brain, with particular reference to the pathogenesis of associated neurological diseases.

scholarly journals Ccr4 is a novel shuttle factor required for ubiquitin-dependent proteolysis by the 26S proteasome

2020 ◽  
Author(s):  
Ganapathi Kandasamy ◽  
Ashis Kumar Pradhan ◽  
R Palanimurugan
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Proteasomal Degradation ◽  
Rna Degradation ◽  
26S Proteasome ◽  
Cellular Proteins ◽  
Cellular Homeostasis ◽  
Substrate Degradation ◽  
Ubiquitin Proteasome

AbstractDegradation of short-lived and abnormal proteins are essential for normal cellular homeostasis. In eukaryotes, such unstable cellular proteins are selectively degraded by the ubiquitin proteasome system (UPS). Furthermore, abnormalities in protein degradation by the UPS have been linked to several human diseases. Ccr4 protein is a known component of the Ccr4-Not complex, which has established roles in transcription, mRNA de-adenylation and RNA degradation etc. Excitingly in this study, we show that Ccr4 protein has a novel function as a shuttle factor that promotes ubiquitin-dependent degradation of short-lived proteins by the 26S proteasome. Using a substrate of the well-studied ubiquitin fusion degradation (UFD) pathway, we found that its UPS-mediated degradation was severely impaired upon deletion of CCR4 in Saccharomyces cerevisiae. Additionally, we show that Ccr4 binds to cellular ubiquitin conjugates and the proteasome. In contrast to Ccr4, most other subunits of the Ccr4-Not complex proteins are dispensable for UFD substrate degradation. From our findings we conclude that Ccr4 functions in the UPS as a shuttle factor targeting ubiquitylated substrates for proteasomal degradation.

scholarly journals E2A protein degradation by the ubiquitin-proteasome system is stage-dependent during muscle differentiation

Oncogene ◽  
2006 ◽  
Vol 26 (3) ◽  
pp. 441-448 ◽  
Author(s):  
L Sun ◽  
J S Trausch-Azar ◽  
A Ciechanover ◽  
A L Schwartz
Keyword(s):  
Protein Degradation ◽  
Ubiquitin Proteasome System ◽  
Muscle Differentiation ◽  
Ubiquitin Proteasome

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.

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