SUMO Modification of Huntingtin and Huntington's Disease Pathology

@article{Steffan2004SUMOMO,
  title={SUMO Modification of Huntingtin and Huntington's Disease Pathology},
  author={Joan S. Steffan and Namita Rani Agrawal and Judit Pallos and Erica Rockabrand and Lloyd C. Trotman and Natalia Slepko and Katalin Illes and Tam{\'a}s Luk{\'a}csovich and Ya-zhen Zhu and Elena Cattaneo and Pier Paolo Pandolfi and Leslie M. Thompson and J. Lawrence Marsh},
  journal={Science},
  year={2004},
  volume={304},
  pages={100 - 104}
}
Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. [] Key Result In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration.
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SUMO-modifying Huntington’s disease

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Strategies to Investigate Ubiquitination in Huntington's Disease

The current approaches used to study the ubiquitination of both soluble Htt as well as insolubilized Htt present in aggregates are examined, and what is known about involved (de)ubiquitinating enzymes are described.

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A number of potential mechanisms that link compromised ubiquitin-proteasome pathway function and neurodegeneration have been proposed and may offer opportunities for therapeutic intervention.

The interplay between the chaperonin TRiC and N-terminal region of Huntingtin mediates Huntington’s Disease aggregation and pathogenesis

Understanding how N17 functions in Htt aggregation and as a general handle for protein quality control will guide design of HD therapeutics.

Huntingtin Ubiquitination Mechanisms and Novel Possible Therapies to Decrease the Toxic Effects of Mutated Huntingtin

The mechanism underlying mHtt degradation by the ubiquitin–proteasome system (UPS) is described, which has been shown to play a more important role than the autophagy–lysosomal pathway.

Protein aggregates in Huntington's disease

Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects

A novel role for ubiquitination is suggested—attenuation of the pathogenic effect of mHtt, suggesting a reduced capacity to cope with the proteotoxic stress in cells expressing the lysineless protein.
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43 References

Enhanced SUMOylation in polyglutamine diseases.

Targeting aggregation in the development of therapeutics for the treatment of Huntington’s disease and other polyglutamine repeat diseases

A discussion of the effect of antibodies, caspase inhibitors, chemical inhibitors, heat-shock proteins, suppressor peptides and transglutaminase inhibitors upon aggregation and disease is presented.

Transcriptional abnormalities in Huntington disease.

Huntington's disease: the challenge for cell biologists.

Polyglutamine Pathogenesis Emergence of Unifying Mechanisms for Huntington's Disease and Related Disorders

Parkin Facilitates the Elimination of Expanded Polyglutamine Proteins and Leads to Preservation of Proteasome Function*

It is demonstrated that parkin reduces proteasome impairment and caspase-12 activation induced by an expanded polyglutamine protein, and it is speculated that Parkin may function to relieve endoplasmic reticulum stress by preserving proteasomes activity in the presence of misfolded proteins.

Huntingtin aggregation and toxicity in Huntington's disease

The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription.

The possibility that expanded repeat htt causes aberrant transcriptional regulation through its interaction with cellular transcription factors which may result in neuronal dysfunction and cell death in HD is raised.

Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation

Huntingtin Is Ubiquitinated and Interacts with a Specific Ubiquitin-conjugating Enzyme*

Using the yeast two-hybrid system, a human ubiquitin-conjugating enzyme (hE2-25K) is identified as a protein that interacts with the gene product for Huntington disease (HD) (Huntingtin) and it is demonstrated that huntingtin is ubiquitinated.