Huntington's disease: Hot on the trail of misfolded proteins' toxic modus operandi

February 19, 2014
Huntingtin begins as a monomer and then self-associates and forms various oligomeric species, which further aggregate together to form the characteristic fibrillar amyloid structure on the right. Credit: K.Shen/Stanford

Proteins are the workhorses of the cell, and their correctly folded three-dimensional structures are critical to cellular functions. Misfolded structures often fail to properly perform these vital jobs, leading to cellular stress and devastating neurodegenerative disorders such as Alzheimer's, Parkinson's and Huntington's disease.

In comparison with the mysteries of Alzheimer's or Parkinson's disease, Huntington's disease has a seemingly simple culprit: an expansion in the polyglutamine (polyQ) tract of a protein called "Huntingtin" (Htt). This polyQ expansion causes the Htt protein to misfold, which triggers a cascade of events—including aggregation of the Htt protein into very stable, fibrillar, amyloid species, and ultimately, neuronal cell death.

"Despite the simplicity of the misfolding involved, we understand very little about why Htt—an essential protein expressed ubiquitously in all human tissue—becomes so toxic when misfolded," said Koning Shen, a grad student working in the Frydman Lab at Stanford University.

Shen will describe her team's multipronged efforts to gain a better understanding of the relationship between protein misfolding, aggregation and cell toxicity at the 58th Annual Biophysical Society Meeting, which takes place Feb. 15-19, 2014, in San Francisco, Calif.

The cause of neuronal toxicity in Huntington's disease remains unknown. Until recently, general consensus had associated fibrillar aggregates with pathogenesis in Huntington's disease. Newer studies, however, point to transient, intermediate species called "oligomers," which occur during the aggregation process, as the key players in neurotoxicity, rather than the fibrillar aggregates.

"Identifying the toxic perpetrators will help explain the pathogenesis of not only Huntington's disease, but perhaps Alzheimer's and Parkinson's as well," explained Shen.

Shen and colleagues also hope to discover which molecular factors may contribute to or ameliorate Htt toxicity. An extended polyQ region is the molecular signature of Htt aggregation, but regions flanking the polyQ tract can also alter the aggregation pathway.

"A molecular chaperone called 'TRiC' can suppress Huntington's disease pathogenesis by binding to one of the polyQ-flanking regions. These flanking regions act as a tool to probe the Htt aggregation pathway to learn how Htt forms toxic aggregate species and how the cell has developed tools to stop it," Shen said. "Altering the regions flanking the polyQ tract could remarkably impact both the aggregation and toxicity of the Huntingtin protein."

Deletions or mutations within these regions may either exacerbate or alleviate aggregation—despite having the same polyQ length. And, Shen pointed out, "fibrillar aggregation and toxicity don't go hand-in-hand amongst these flanking mutants. This finding suggests that there may be toxic intermediate species manifested through the polyQ region, which can be modulated by the polyQ-flanking regions."

Since these flanking region modulations are independent of polyQ length, the ability to use these regions for small molecule or peptide therapeutics delivery will be powerful for Huntington's disease patients, who have already been expressing polyQ-expanded Htt for many years of their lives.

"By manipulating these flanking regions, we may be able to directly influence the aggregation pathway in Huntington's disease patients," said Shen. "Because TRiC binding to a polyQ flanking region suppresses pathogenesis, the interaction between TRiC and Htt shows great potential for therapeutics development."

Recent work has highlighted the ability of a domain of TRiC, called "Apical1," to exhibit TRiC-like effects at suppressing Htt pathogenesis. "This small domain can be more easily adapted into peptide therapeutics and administered to Huntington's disease patients. If developed with an understanding of the toxicity of these misfolded proteins, this next generation of therapeutics may emerge within the next 5 to 10 years," Shen noted.

Explore further: Staying ahead of Huntington's disease

More information: The presentation "Polyglutamine Flanking Regions in Huntingtin Highlight Key Structural Intermediates Relevant for Molecular Chaperone Interaction and Huntington's Disease Pathogenesis"" by Koning Shen, Barbara Calamini, Donald Lo and Judith Frydman will be at 10:30 a.m. on Wednesday, February 19, 2014 in Hall D in San Francisco's Moscone Convention Center. Abstract:

Related Stories

Staying ahead of Huntington's disease

December 11, 2013
Huntington's disease is a devastating, incurable disorder that results from the death of certain neurons in the brain. Its symptoms show as progressive changes in behavior and movements.

New insight into the cellular defects in Huntington's disease

October 10, 2011
Huntington disease is a devastating neurogenerative disorder that causes a progressive loss of functional capacity and reduced life span. It is an inherited condition caused by a mutant HTT gene. Although this has been known ...

Having Huntington's disease or other 'polyQ' diseases protects against cancer, suggesting common genetic mechanism

April 11, 2012
Having Huntington's disease or other diseases known as polyglutamine (polyQ) diseases reduces a person's risk of getting cancer, suggesting a common genetic mechanism, concludes an Article published Online First by The Lancet ...

Recommended for you

Researchers develop treatment to reduce rate of cleft palate relapse complication

September 22, 2017
Young people with cleft palate may one day face fewer painful surgeries and spend less time undergoing uncomfortable orthodontic treatments thanks to a new therapy developed by researchers from the UCLA School of Dentistry. ...

Exosomes are the missing link to insulin resistance in diabetes

September 21, 2017
Chronic tissue inflammation resulting from obesity is an underlying cause of insulin resistance and type 2 diabetes. But the mechanism by which this occurs has remained cloaked, until now.

Thousands of new microbial communities identified in human body

September 20, 2017
A new study of the human microbiome—the trillions of microbial organisms that live on and within our bodies—has analyzed thousands of new measurements of microbial communities from the gut, skin, mouth, and vaginal microbiome, ...

Study finds immune system is critical to regeneration

September 20, 2017
The answer to regenerative medicine's most compelling question—why some organisms can regenerate major body parts such as hearts and limbs while others, such as humans, cannot—may lie with the body's innate immune system, ...

Immune cells produce wound healing factor, could lead to new IBD treatment

September 20, 2017
Specific immune cells have the ability to produce a healing factor that can promote wound repair in the intestine, a finding that could lead to new, potential therapeutic treatments for inflammatory bowel disease (IBD), according ...

As men's weight rises, sperm health may fall

September 20, 2017
(HealthDay)—A widening waistline may make for shrinking numbers of sperm, new research suggests.


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.