Posts tagged chromosomes
Articles and news from the latest research reports.
Scientists Identify Early Predictors of Disease Progression Which Could Speed Huntington’s Disease Drug Trials
Scientists have identified a set of tests that could help identify whether and how Huntington’s disease (HD) is progressing in groups of people who are not yet showing symptoms. The latest findings from the TRACK-HD study*, published Online First in The Lancet Neurology, could be used to assess whether potential new treatments are slowing the disease up to 10 years before the development of noticeable symptoms.
“Currently, the effectiveness of a new drug is decided by its ability to treat symptoms. These new tests could be used in future preventative drug trials in individuals who are gene positive for HD but are not yet showing overt motor symptoms. These people have the most to gain by initiating treatment early to delay the start of these overt symptoms and give them a high quality of life for a longer period of time”, explains lead author Sarah Tabrizi from University College London’s Institute of Neurology.
The TRACK-HD investigators have previously reported a range of tests that could be used in clinical trials to assess the effectiveness of potential disease-modifying drugs in people who already show signs of the disease. But in individuals without noticeable symptoms there was little evidence of a decline in function over two years, limiting the ability to test new drugs early in the disease course.
HD is caused by the mutation of a single gene on chromosome 4, which causes a part of the DNA (known as a CAG motif) to repeat many more times than it is supposed to. The length of the CAG repeat is known to be a major determinant of the age at which symptoms of the disease are likely to start, but its contribution to progression is unclear.
Here the TRACK-HD investigators extend the study to a third year with the aim of identifying some of the earliest biological changes in individuals with presymptomatic HD, giving additional power to predict how the disease may progress beyond that already expected from age and CAG length.
Over 3 years, baseline measures derived from brain imaging were the clearest markers of disease progression and future diagnosis, above and beyond the effect of age and CAG count, in gene carriers up to 20 years before they were expected to show symptoms.
In particular, the investigators suggest that measuring volume change in white matter and the caudate and putamen regions might be future endpoints for treatment trials.
In individuals up to 10 years away from developing symptoms, there was also significant deterioration in performance on a number of motor (movement) and cognitive (intellectual function) tasks compared with controls, and the frequency of apathy increased. Finger tapping was the most sensitive of the motor assessments, while the symbol digit modality test proved to be the most sensitive of the cognitive measures.
According to Tabrizi, “A new generation of drugs will be ready for human trials in the very near future. Diagnosis in HD is something of an artificial construct at onset of motor symptoms, and this study now gives us a number of other, more well-defined parameters that correlate with disease progression. Something that suggests we’re moving towards a more biological, as opposed to physical, definition of disease progression that reduces the importance of an ‘onset event’ is great news. By extending the reach of clinical trials to include individuals who are currently free of overt symptoms there is a realistic future possibility that treatments in the pipeline can significantly improve the quality of life for patients and families.”**
Writing in a linked Comment, Francis O. Walker, M.D., from Wake Forest School of Medicine in the USA says that the TRACK-HD investigators have set the standard for observational studies in other neurodegenerative diseases, adding that, “Virtual roadmaps of disease in the minds of practitioners are good for care in the framework of the traditional patient encounter, but it takes substantial effort, teamwork, and genius to turn them into rigorous, quantifiable timelines that can be used to test efficacy in future therapeutic trials.”
* The Track-HD study was established to identify differences between people carrying the HD mutation at different stages and healthy controls that could be used to accurately predict the progression of HD using a variety of techniques to assess changes in brain function, motor function, behaviour, and cognition. 366 individuals from Canada, France, the Netherlands and the UK were enrolled: 120 presymptomatic carriers of the HD gene mutation, 123 patients with early symptomatic HD, and 123 healthy controls.
(Source: newswise.com)
Cell biologists show molecular forces are key to proper cell division
Studies led by assistant professor of Biology Thomas Maresca are revealing new details about a molecular surveillance system that helps detect and correct errors in cell division that can lead to cell death or human diseases. Findings are reported in the current issue of the Journal of Cell Biology.
The purpose of cell division is to evenly distribute the genome between two daughter cells. To achieve this, every chromosome must properly interact with a football-shaped structure called the spindle. However, interaction errors between the chromosomes and spindle during division are amazingly common, occurring in 86 to 90 percent of chromosomes, says Maresca, an expert in mitosis.
“This is not quite so surprising when you realize that every single one of the 46 chromosomes has to get into perfect position every time a cell divides,” he notes. The key to flawless cell division is to correct dangerous interactions before the cell splits in two.
Working with fruit fly tissue culture cells, Maresca and graduate students Stuart Cane and Anna Ye have developed a way to watch and record images of the key players in cell division including microtubule filaments that form the mitotic spindle and sites called kinetochores that mediate chromosome-microtubule interactions. They also examined the contribution of a force generated by molecular engines called the polar ejection force (PEF), which is thought to help line up the chromosomes in the middle of the spindle for division. For the first time, they directly tested and quantified how PEF, in particular, influences tension at kinetochores and affects error correction in mitosis.
“We also now have a powerful new assay to get at how this tension regulates kinetochore-microtubule interactions,” Maresca adds. “We knew forces and tension regulated this process, but we didn’t understand exactly how. With the new technique, we can start to dissect out how tension modulates error correction to repair the many erroneous attachment intermediates that form during division.”
Separation of a cell
This illustration shows a cell undergoing mitosis or “cell division.” The cell membrane is shown in blue, and the cell’s chromosomes are shown in yellow. Mitosis is a well-studied and well-imaged phenomenon in two-dimensional images, but it’s never before been seen quite like this. What makes this image special is the use of a new fluorescent protein called MiniSOG, shown flying out of the cell.
Image courtesy of Andrew Noske and Thomas Deerinck (National Center for Microscopy and Imaging Research, University of California, San Diego); Horng Ou and Clodagh O’Shea (Salk Institute).
(Source: MSNBC)
Extra chromosome 21 removed from Down syndrome cell line
University of Washington scientists have succeeded in removing the extra copy of chromosome 21 in cell cultures derived from a person with Down syndrome, a condition in which the body’s cells contain three copies of chromosome 21 rather than the usual pair.
A triplicate of any chromosome is a serious genetic abnormality called a trisomy. Trisomies account for almost one-quarter of pregnancy loss from spontaneous miscarriages, according to the research team. Besides Down syndrome (trisomy 21), some other human trisomies are extra Y or X chromosomes, and Edwards syndrome (trisomy 18) and Patau syndrome (trisomy 13), both of which have extremely high newborn fatality rates.
In their report appearing in the Nov. 2 edition of Cell Stem Cell, a team led by Dr. Li B. Li of the UW Department of Medicine described how they corrected trisomy 21 in human cell lines they grew in the lab. The senior scientists on the project were gene therapy researchers Dr. David W. Russell, professor of medicine and biochemistry, and Dr. Thalia Papayannopoulou, professor of medicine.
The targeted removal of a human trisomy, they noted, could have both clinical and research applications.
Scientists peek at the early evolution of sex chromosomes
Two new studies offer insight into sex chromosome evolution by focusing on papaya, a multimillion dollar crop plant with a sexual problem (as far as growers are concerned) and a complicated past.
The research reveals that the papaya sex chromosomes have undergone dramatic changes in their short evolutionary histories (they are about 7 million years old; by comparison, human sex chromosomes began their evolution more than 167 million years ago). One of the two studies compares the papaya X chromosome with that of a closely related non-sex chromosome (called an autosome) in a sister species. The other looks at differences between the X and Y chromosomes.