Huntington's Disease Peptides: polyQ-hHtt Fragments

Overview

Huntington's Disease (HD) is an autosomal disease characterized by the aggregation of proteins containing long stretches of consecutive polyglutamine (polyQ), which are encoded by a mutated huntingtin gene (htt). These proteins are called human huntingtin protein, polyQ-hHtt. HD victims suffer from motor and cognitive dysfunction, which lead to dementia and subsequent death.

The Origins of polyQ-hHtt

The expression of the HD protein, polyQ-hHtt, is a result of the expansion of the trinucleotide sequence, CAG, in the htt gene. The expansion to 35 or more CAG triplets results in production of polyQ-hHtt. The polyQ domain of polyQ-hHtt causes misfolding of the protein, making it prone to self-aggregation. Although the aggregates are predominantly nuclear, some aggregates form outside of the nucleus. These aggregates contribute to neuronal degeneration and the progression of HD.

Peptides in HD Therapeutic Research

Similar to the peptides of Alzheimer's Disease, Huntington's Disease peptides can be used for:

• The design of aggregative inhibitors of polyQ-hHtt.
• The development of vaccines to promote immune clearance of aggregative polyQ-hHtt proteins.
• The study of polyQ-hHtt dynamics.

• Mishra R., Jayaraman M., Roland B.P., Landrum E., Fullam T., Kodali R., Thakur A.K., Arduini I., Wetzel R. (2012) Inhibiting the nucleation of amyloid structure in a huntingtin fragment by targeting α-helix-rich oligomeric intermediates. J Mol Biol. 415: 900-917.
• Jayaraman M., Kodali R., Sahoo B., Thakur A.K., Mayasundari A., Mishra R., Peterson C.B., Wetzel R. (2012) Slow amyloid nucleation via α-helix-rich oligomeric intermediates in short polyglutamine-containing huntingtin fragments. J Mol Biol. 415: 881-899.
• Atwal R.S., Xia J., Pinchev D., Taylor, J. Epand R.M., and Truant R. (2007) Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity.. Hum Mol Genet. 16: 2600 – 2615.

Huntington's Disease Peptide Research Toolbox