Huntingtin Protein and Protein Aggregation
Part 9

What Causes the Onset of HD?

Future Challenges for Huntingtin Research

Clearly, we have much to learn from exploring the relationships between the Huntington gene, huntingtin protein, protein aggregation, and neural cell death that characterize HD. The effects of HD huntingtin protein on the CBP and UPS pathways are examples of molecular-level problems leading to neural cell death. Future research in this area will likely continue to explore the following questions:

• What is the process by which the proteins aggregate?
• How can the cell get rid of these aggregates?
• What other protein-protein interactions are involved in this disease?

Answers to these questions may point to further possibilities for treatment of HD.

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C. Barnard, 1-28-02

For further reading:

1. Bence NF, Sampat RM, Kopito RR. "Impairment of the ubiquitin-proteasome system by protein aggregation." Science 2001. 292: 1552-1555.
   A fairly technical paper, reporting a study which shows that protein aggregation impairs the ubiquitin-proteasome system.
2. Helmuth, Laura. "Protein clumps hijack cell’s clearance system." Science 2001. 292: 1467-1468.
   A less technical, more reader-friendly summary of the paper listed above.
3. Kopito RR, Ron D. "Conformational disease." Nature Cell Biology. 2: 207-209.
   A fairly technical overview of diseases caused by protein aggregation pathways.
4. Nucifora FC, Jr, et al. "Interference by huntingtin and atrophin-1 with CBP-medicated transcription leading to cellular toxicity." Science 2001. 291(5512): 2423-2428.
   A highly technical paper regarding the negative effect produced when the altered huntingtin protein “kidnaps” a smaller protein called CBP.
5. Steffan JS, et al. "Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila." Nature 2001. 413: 739-743.
   A fairly technical paper that discusses the interaction between altered huntingtin protein and CBP, as well as the effects of HDAC inhibitors.
6. Waelter S et al. “Accumulation of mutant huntingtin fragments in aggresome-like inclusion bodies as a result of insufficient protein degradation.” Molecular Biology of the Cell 2001. 12(5): 1393-1407.
   A fairly technical paper regarding the relationship between inclusion bodies and the ubiquitin-proteasome system.

Last Modified: 9-13-02

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