Study by Tufts biologist provides window into progression of some degenerative diseases

July 22, 2004

MEDFORD/SOMERVILLE, Mass. - A Tufts University study has shed light on how some inherited diseases such as Huntington's and muscular dystrophy develop in humans.

"Our findings show a possible reason that cells with a certain type of mutation (expansion of repetitive DNA) die prematurely," said Catherine Freudenreich, assistant professor of biology at the School of Arts and Sciences at Tufts. "We may be able to use this information to stop or slow the development of some of these degenerative diseases that affect thousands of people every year."

She and her colleagues - post-doctoral fellow Mayurika Lahiri and former Tufts undergraduate researchers Tanya Gustafson and Elizabeth Majors - published their findings, "Expanded CAG repeats activate the DNA damage checkpoint pathway" in the July 23 issue of the journal Molecular Cell.

Freudenreich, a molecular biologist, studies the unstable elements in the human genome, particularly the type of unstable element called "trinucleotide repeat sequences," whose expansion causes numerous human genetic diseases such as Huntington's disease (a degenerative neurological disease) and myotonic dystrophy (a type of muscular dystrophy). There are more than 15 repeat expansion diseases, all of which are of special interest because they are caused by a highly unusual DNA mutation, one in which a repetitive DNA sequence expands from a small number of copies to a larger number. For example, 20 copies of a DNA sequence (such as CAG) could expand to 70 or 100 copies to cause disease.

With a grant for more than $1 million from the National Institutes of Health, Freudenreich's team investigated whether the presence of expanded repeats in a cell is recognized by the cell as damage and, if so, whether the cell activates the surveillance system that facilitates repair (called the "DNA damage checkpoint pathway"). They found that the proteins that signal that DNA damage is present are activated when a cell contains an expanded CAG repeat sequence.

"We know this because when we used cells that were defective in the checkpoint proteins, there was a large increase in chromosome breakage at the expanded repeat. This means that cells with expanded repeats are particularly vulnerable and if their surveillance mechanism fails for any reason they will probably die. This is important because cell death is a hallmark of most of the CAG expansion diseases, leading to neurodegeneration in Huntington's disease and muscle degeneration in myotonic dystrophy."

Although some of the reasons for the degeneration are understood, activation of the checkpoint pathway is a possible contributor that wasn't recognized before.

In the study, the researchers also found that when some checkpoint proteins were absent, the CAG repeat became very instable, contracting at an increased frequency. This means the checkpoint status of a cell can influence repeat stability.

"This is interesting because it still isn't understood why the repeat doesn't change size in some cell types, but is very unstable in others," Freudenreich said.

For example, in Huntington's disease the repeat is prone to expansion during sperm development, which leads to inheritance of even longer repeats in the resulting children and a worsening of the disease in the next generation. The CAG repeat also expands further in the affected brain cells of patients, which could explain why those brain cells die first. So identification of factors that limit expansion, such as these checkpoint proteins, could be very useful in controlling the inheritance and severity of the repeat expansion diseases.

"Freudenreich's study is an example of the innovative genetic research being done at Tufts and it will have long-term impact on future understanding of the mechanisms responsible for genomic instability and their relationship with certain inherited diseases," said Susan Ernst, dean of the School of Arts and Sciences at Tufts and a professor of biology.
-end-
EDITORS NOTE: Here is a link to Freudenreich's web page at Tufts: http://ase.tufts.edu/BIOLOGY/faculty/bios/freudenreich/freudenreich.html

Tufts University, located on three Massachusetts campuses in Boston, Medford/Somerville, and Grafton, and in Talloires, France, is recognized among the premier research universities in the United States. Tufts enjoys a global reputation for academic excellence and for the preparation of students as leaders in a wide range of professions. A growing number of innovative teaching and research initiatives span all Tufts campuses, and collaboration among the faculty and students in the undergraduate, graduate and professional programs across the University's eight schools is widely encouraged.

Tufts University

Related Muscular Dystrophy Articles from Brightsurf:

Using CRISPR to find muscular dystrophy treatments
A study from Boston Children's Hospital used CRISPR-Cas9 to better understand facioscapulohumeral muscular dystrophy (FSHD) and explore potential treatments by systematically deleting every gene in the genome.

Duchenne muscular dystrophy diagnosis improved by simple accelerometers
Testing for Duchenne muscular dystrophy can require specialized equipment, invasive procedures and high expense, but measuring changes in muscle function and identifying compensatory walking gait could lead to earlier detection.

New therapy targets cause of adult-onset muscular dystrophy
The compound designed at Scripps Research, called Cugamycin, works by recognizing toxic RNA repeats and destroying the garbled gene transcript.

Gene therapy cassettes improved for muscular dystrophy
Experimental gene therapy cassettes for Duchenne muscular dystrophy have been modified to deliver better performance.

Discovery points to innovative new way to treat Duchenne muscular dystrophy
Researchers at The Ottawa Hospital and the University of Ottawa have discovered a new way to treat the loss of muscle function caused by Duchenne muscular dystrophy in animal models of the disease.

Extracellular RNA in urine may provide useful biomarkers for muscular dystrophy
Massachusetts General Hospital researchers have found that extracellular RNA in urine may be a source of biomarkers for the two most common forms of muscular dystrophy, noninvasively providing information about whether therapeutic drugs are having the desired effects on a molecular level.

Tamoxifen and raloxifene slow down the progression of muscular dystrophy
Steroids are currently the only available treatment to reduce the repetitive cycles of inflammation and disease progression associated with functional deterioration in patients with muscular dystrophy (MD).

Designed proteins to treat muscular dystrophy
The cell scaffolding holds muscle fibers together and protects them from damage.

Gene-editing alternative corrects Duchenne muscular dystrophy
Using the new gene-editing enzyme CRISPR-Cpf1, researchers at UT Southwestern Medical Center have successfully corrected Duchenne muscular dystrophy in human cells and mice in the lab.

GW researcher finds genetic cause of new type of muscular dystrophy
George Washington University & St. George's University of London research, published in The American Journal of Human Genetics, outlines a newly discovered genetic mutation associated with short stature, muscle weakness, intellectual disability, and cataracts, leading researchers to believe this is a new type of congenital muscular dystrophy.

Read More: Muscular Dystrophy News and Muscular Dystrophy Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.