The roles of intracellular protein-degradation pathways in neurodegeneration

@article{Rubinsztein2006TheRO,
  title={The roles of intracellular protein-degradation pathways in neurodegeneration},
  author={David C. Rubinsztein},
  journal={Nature},
  year={2006},
  volume={443},
  pages={780-786}
}
Many late-onset neurodegenerative diseases, including Parkinson's disease and Huntington's disease, are associated with the formation of intracellular aggregates by toxic proteins. It is therefore crucial to understand the factors that regulate the steady-state levels of these 'toxins', at both the synthetic and degradation stages. The degradation pathways acting on such aggregate-prone cytosolic proteins include the ubiquitin–proteasome system and macroautophagy. Dysfunction of the ubiquitin… 

Figures from this paper

Role of the ubiquitin–proteasome system and autophagy in polyglutamine neurodegenerative diseases
TLDR
This article reviews recent studies that have shown a critical role of the ubiquitin–proteasome system and autophagy in the pathogenesis of polyglutamine diseases and suggests that understanding the role of these two pathways in disease pathogenesis could open up a new attractive therapeutic avenue for polyglUTamine and other related neurodegenerative disorders.
The Role of Autophagy in Age-Related Neurodegeneration
TLDR
Autophagy is described and recent evidence indicating that autophagy may be exploited to remove toxic protein species, suggesting novel strategies for therapeutic intervention for a class of diseases for which no effective treatments presently exist is reviewed.
Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases
TLDR
Recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer's disease, Parkinson’s disease, and Huntington's disease are reviewed.
The Ubiquitin-Proteasome Pathway in Huntington's Disease
TLDR
A number of potential mechanisms that link compromised ubiquitin-proteasome pathway function and neurodegeneration have been proposed and may offer opportunities for therapeutic intervention.
Autophagy and misfolded proteins in neurodegeneration
Advances in Proteasome Enhancement by Small Molecules
TLDR
This review discusses the structure of proteasome and how prote asome’s proteolytic activity is associated with aging and various neurodegenerative diseases, and summarizes various classes of compounds that are capable of enhancing, directly or indirectly, proteasomesome-mediated protein degradation.
Mechanism and Regulation of Autophagy and Its Role in Neuronal Diseases
TLDR
Understanding is still incomplete but may highlight up-to-date findings on how autophagy is executed and regulated at the molecular level and its role in neurodegenerative diseases, hence providing attractive new avenues for the development of treatment strategies to combat neuronal diseases.
The role of autophagy-lysosome pathway in neurodegeneration associated with Parkinson's disease.
TLDR
The demonstration that alpha-synuclein is degraded by both proteasome and autophagy indicates a possible linkage between the dysfunction of the UPS or ALP and the occurrence of Parkinson's disease.
Ubiquitin, the proteasome and protein degradation in neuronal function and dysfunction
TLDR
The molecular mechanism of protein degradation in the neuron with respect to both its function and its dysfunction is discussed, highlighting the importance and vulnerability of the degradative system in neurons.
Chemical Inducers of Autophagy That Enhance the Clearance of Mutant Proteins in Neurodegenerative Diseases*
TLDR
This minireview will consider the reasons why autophagy up-regulation may be a powerful strategy for neurodegenerative diseases such as Parkinson disease, tauopathies, and polyglutamine expansion diseases, and some of the drugs and associated signaling pathways that can be used to induceAutophagy with these therapeutic aims in mind.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 87 REFERENCES
Impairment of the ubiquitin-proteasome system by protein aggregation.
TLDR
It is reported that protein aggregation directly impaired the function of the ubiquitin-proteasome system, suggesting a potential mechanism linking protein aggregation to cellular disregulation and cell death.
Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
TLDR
It is found that wild-type α-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway, which may underlie the toxic gain-of-function by the A53T and A30P mutants.
Rapamycin alleviates toxicity of different aggregate-prone proteins.
TLDR
The studies suggest that the scope for rapamycin as a potential therapeutic in aggregate diseases may be much broader than HD or even polyglutamine diseases.
Increased susceptibility of cytoplasmic over nuclear polyglutamine aggregates to autophagic degradation.
TLDR
It is shown that autophagy is essential for the elimination of aggregated forms of mutant huntingtin and ataxin-1 from the cytoplasmic but not nuclear compartments, and may help to explain why protein aggregates are more toxic when directed to the nucleus.
Toxic Proteins in Neurodegenerative Disease
TLDR
Increased understanding of the cellular mechanisms for disposal of abnormal proteins and of the effects of toxic protein accumulation on neuronal survival may allow the development of rational, effective treatment for neurodegenerative disorders.
What is the role of protein aggregation in neurodegeneration?
TLDR
It is suggested that protein aggregation is pathogenic, but several lines of evidence indicate that inclusion bodies are not the main cause of toxicity, and probably represent a cellular protective response.
Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway
TLDR
Findings indicate that the accumulation of mutant protein can lead to mTOR-independent macroautophagy and that lysosome-mediated degradation of accumulated protein differs from degradation under conditions of starvation.
Aggregate-prone proteins with polyglutamine and polyalanine expansions are degraded by autophagy.
TLDR
Exon 1 of the HD gene with expanded polyglutamine [poly(Q)] repeats and enhanced green fluorescent protein tagged to 19 alanines is used as models for aggregate-prone proteins, to investigate the pathways mediating their degradation and re-examined the role of the proteasome.
Aggregate formation inhibits proteasomal degradation of polyglutamine proteins.
TLDR
Introduction of a degradation signal in ataxin-1/Q92 reduced the incidence of nuclear inclusions and the cellular toxicity, conceivably by accelerating the clearance of the soluble substrate.
The ubiquitin pathway in Parkinson's disease
TLDR
It is shown that in a German family with Parkinson's disease a missense mutation in the ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) gene causes a partial loss of the catalytic activity of this thiol protease, which could lead to aberrations in the proteolytic pathway and aggregation of proteins.
...
1
2
3
4
5
...