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Subject: SMALL CHANGES IN PROTEIN CHEMISTRY PLAY LARGE ROLE IN HUNTINGTON'S
DISEASE

U.S. Department of Health and Human Services 
NATIONAL INSTITUTES OF HEALTH NIH News 
National Institute of Neurological Disorders and Stroke
(NINDS)<http://www.ninds.nih.gov/>
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Embargoed for Release: Thursday, December 24, 2009, Noon, EST 

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SMALL CHANGES IN PROTEIN CHEMISTRY PLAY LARGE ROLE IN HUNTINGTON'S DISEASE

Small Changes in Protein Chemistry Play Large Role in Huntington's Disease 
In Huntington's disease, a mutated protein in the body becomes toxic to
brain cells. Recent studies have demonstrated that a small region adjacent
to the mutated segment plays a major role in the toxicity. Two new studies
supported by the National Institutes of Health show that very slight changes
to this region can eliminate signs of Huntington's disease in mice.

Researchers do not fully understand why the protein (called mutant
huntingtin) is toxic, but one clue is that it accumulates in ordered clumps
of fibrils, perhaps clogging up the cells' internal machinery. 

"These studies shed light on the structure and biochemistry of the mutant
huntingtin protein and on potentially modifiable factors that affect its
toxicity," said Margaret Sutherland, Ph.D., a program director at NIH's
National Institute of Neurological Disorders and Stroke (NINDS). "They
reveal sites within the huntingtin protein and within broader disease
pathways that could serve as targets for drug therapy."

Both studies were published online this week. One study, published in the
Journal of Cell Biology, was led by Leslie Thompson, Ph.D., and Joan
Steffan, Ph.D., of the University of California, Irvine. The other study, in
Neuron, was led by X. William Yang, M.D., Ph.D., of the University of
California, Los Angeles in collaboration with Ron Wetzel, Ph.D., of the
University of Pittsburgh School of Medicine.

Huntington's disease is inherited, and usually strikes in middle age,
producing uncontrollable movements of the legs and arms, a loss of muscle
coordination, and changes in personality and intellect. It is inexorably
progressive and leads to death of affected persons usually within 20 years
after symptoms first appear. Individuals with the disease carry mutations
that affect the huntingtin protein. The mutations involve a triple repeat
DNA sequence, a type of genetic miscue similarly found in Friedreich's
ataxia, Kennedy's disease, fragile X syndrome, and other neurodegenerative
disorders. 

The normal huntingtin protein consists of about 3,150 amino acids (which are
the building blocks for all proteins). In individuals with Huntington's
disease, the mutated protein contains an abnormally long string of a single
amino acid repeat; lengthier chains are associated with worse symptoms and
earlier onset of the disease. In recent years, however, researchers have
begun looking at the effects of other, nearby amino acids in this large
protein - and in particular, biochemical changes to those amino acids.

In their study, Drs. Steffan and Thompson investigated how a process called
phosphorylation affects huntingtin. Phosphorylation is the attachment of
chemical tags, known as phosphates, onto the amino acids in a protein. The
process occurs naturally and is a way of marking proteins for destruction by
cellular waste handling systems. The researchers liken it to putting a sign
on a pile of junk that tells the garbage collectors to take it away. Their
study shows that phosphorylation of just two amino acids, located at one end
of huntingtin, targets the protein for destruction and protects against the
toxic effects of the mutant protein. 

"Clearance of mutant huntingtin is likely regulated at many levels, but our
data establish that these two amino acids are critical," Dr. Steffan said.

Could boosting phosphorylation of those two amino acids reduce the buildup
of huntingtin and improve symptoms of the disease? In parallel with the UC
Irvine research, Dr. Yang and his team at UCLA were asking that question
using an animal model of Huntington's disease. Previously, Dr. Yang had
created mice that carry the mutant huntingtin gene. These mice develop
symptoms reminiscent of Huntington's disease in humans, including poor
coordination, mental changes such as increased anxiety, loss of brain
tissue, and accumulation of clumps of huntingtin in brain cells.

Through further genetic engineering, Dr. Yang altered the same two critical
amino acids at the end of the mutant huntingtin protein to either mimic
phosphorylation (phosphomimetic) or resist it (phosphoresistant). Mice with
the phosphoresistant version of the protein developed symptoms of
Huntington's, but mice with the phosphomimetic version remained free of
symptoms and huntingtin clumps up to one year. 

Meanwhile, test tube experiments by Dr. Wetzel's group in Pittsburgh showed
that phosphomimetic modification of a huntingtin fragment reduced its
tendency to form clumps. Together, data from the mouse and test tube
experiments provide strong support for the idea that phosphorylation acts as
a molecular switch to alter clumping of the mutant protein, the researchers
said. 

The nearly complete lack of any signs of disease in the phosphomimetic
Huntington mice may point toward new strategies to treat the disorder
someday. Dr. Yang said, "Drugs that enhance or mimic the effects of
phosphorylation may help to detoxify the mutant huntingtin protein."

If such drugs could be developed, Drs. Steffan and Thompson theorize, they
would likely be most effective at early stages of the disease, but less so
at later stages, when the clearance machinery appears to run down. Dr. Yang
said he plans to examine older mice carrying the phosphomimetic version of
mutant huntingtin to determine how long they are protected from the disease.

The researchers received major funding from NINDS, with additional support
from the National Institute on Aging, the Eunice Kennedy Shriver National
Institute of Child Health and Human Development, and the National Institute
of General Medical Sciences. Several nonprofit foundations also contributed
to the research, including the Hereditary Disease Foundation, the Fox Family
Foundation and CHDI Inc.

Co-authors of the Journal of Cell Biology study included J. Lawrence Marsh,
Ph.D. and Lan Huang, Ph.D., at UC Irvine; Ana Maria Cuervo, M.D., Ph.D., at
Albert Einstein College of Medicine, New York City; Donald C. Lo, Ph.D. at
Duke University, Durham, N.C.; Paul H. Patterson, Ph.D., at California
Institute of Technology, Pasadena; and Steven Finkbeiner, M.D., Ph.D., at
the University of California, San Francisco. 

Co-authors of the Neuron study included Xiaofeng Gu, M.D., Ph.D., and Erin
Greiner at UCLA; Rakesh Mishra and Ravindra Kodali, Ph.D., at the University
of Pittsburgh; Alex Osmand, Ph.D., at the University of Tennessee,
Knoxville; and Dr. Finkbeiner at UCSF.

NINDS (www.ninds.nih.gov) is the nation's primary supporter of biomedical
research on the brain and nervous system. NIA (www.nia.nih.gov) leads the
federal effort supporting and conducting research on aging and the medical,
social and behavioral issues of older people. NICHD (www.nichd.nih.gov)
sponsors research on development, before and after birth; maternal, child,
and family health; reproductive biology and population issues; and medical
rehabilitation. NIGMS (www.nigms.nih.gov) supports basic biomedical research
that is the foundation for advances in disease diagnosis, treatment and
prevention.

For more information about Huntington's disease, visit
<http://www.ninds.nih.gov/disorders/huntington/huntington.htm>.

The National Institutes of Health (NIH) -- The Nation's Medical Research
Agency -- includes 27 Institutes and Centers and is a component of the U.S.
Department of Health and Human Services. It is the primary federal agency
for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and its programs,
visit <www.nih.gov>.
------------------------
REFERENCES:
Thompson, Leslie M. et al. "IKK phosphorylates Huntingtin and Targets it for
Degradation by the Proteasome and Lysosome." Journal of Cell Biology,
published online Dec. 21, 2009.

Gu, Xiaofeng et al. "Serines 13 and 16 Are Critical Determinants of
Full-length Human Mutant Huntingtin-Induced Disease Pathogenesis in HD
Mice." Neuron, published online Dec. 24, 2009.
  
##

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