Posts tagged huntington's disease
Articles and news from the latest research reports.
BUSM Study Identifies Pathology of Huntington’s Disease
A study led by researchers at Boston University School of Medicine (BUSM) provides novel insight into the impact that Huntington’s disease has on the brain. The findings, published online in Neurology, pinpoint areas of the brain most affected by the disease and opens the door to examine why some people experience milder forms of the disease than others.
Richard Myers, PhD, professor of neurology at BUSM, is the study’s lead/corresponding author. This study, which is the largest to date of brains specific to Huntington’s disease, is the product of nearly 30 years of collaboration between the lead investigators at BUSM and their colleagues at the McLean Brain Tissue Resource Center, Massachusetts General Hospital and Columbia University.
Huntington’s disease (HD) is an inherited and fatal neurological disorder that typically is diagnosed when a person is approximately 40 years old. The gene responsible for the disease was identified in 1993, but the reason why certain neurons or brain cells die remains unknown.
The investigators examined 664 autopsy brain samples with HD that were donated to the McLean Brain Bank. They evaluated and scored more than 50 areas of the brain for the effects of HD on neurons and other brain cell types. This information was combined with a genetic study to characterize variations in the Huntington gene. They also gathered the clinical neurological information on the patients’ age when HD symptoms presented and how long the patient survived with the disease.
Based on this analysis, the investigators discovered that HD primarily damages the brain in two areas. The striatum, which is located deep within the brain and is involved in motor control and involuntary movement, was the area most severely impacted by HD. The outer cortical regions, which are involved in cognitive function and thought processing, also showed damage from HD, but it was less severe than in the striatum.
The investigators identified extraordinary variation in the extent of cell death in different brain regions. For example, some individuals had extremely severe outer cortical degeneration while others appeared virtually normal. Also, the extent of involvement for these two regions was remarkably unrelated, where some people demonstrated heavy involvement in the striatum but very little involvement in the cortex, and vice versa.
“There are tremendous differences in how people with Huntington’s disease are affected,” Myers said. “Some people with the disease have more difficulty with motor control than with their cognitive function while others suffer more from cognitive disability than motor control issues.”
When studying these differences, the investigators noted that the cell death in the striatum is heavily driven by the effects of variations in the Huntington gene itself, while effects on the cortex were minimally affected by the HD gene and are thus likely to be a consequence of other unidentified causes. Importantly, the study showed that some people with HD experienced remarkably less neuronal cell death than others.
“While there is just one genetic defect that causes Huntington’s disease, the disease affects different parts of the brain in very different ways in different people,” said Myers. “For the first time, we can measure these differences with a very fine level of detail and hopefully identify what is preventing brain cell death in some individuals with HD.”
The investigators have initiated extensive studies into what genes and other factors are associated with the protection of neurons in HD, and they hope these protective factors will point to possible novel treatments.
(Source: bumc.bu.edu)
A new light-based technique for measuring levels of the toxic protein that causes Huntington’s disease (HD) has been used to demonstrate that the protein builds up gradually in blood cells. Published in the Journal of Clinical Investigation, the findings shed light on how the protein causes damage in the brain, and could be useful for monitoring the progression of HD, or testing new drugs aimed at suppressing production of the harmful protein.
Sheep backpacks reveal flocking strategy
UK researchers have shown for the first time that instead of fleeing randomly when faced with danger, sheep head straight for the center of the flock.
Understanding this behavior in healthy animals may help researchers understand the breakdown in social behaviours caused by neurological disorders in sheep, as well as those in humans, such as Huntington’s disease.
The findings support a 40-year-old idea put forward by evolutionary biologist Bill Hamilton. He suggested that creatures as different as insects, fish and cattle all react to danger by moving towards the middle of their respective swarms, schools or herds. “Scientists agree that flocking behavior has evolved in response to the risk of being attacked by predators.
The idea is that being part of a tight-knit group not only increases the chances that you might spot a predator, but decreases the chance that you are the one the predator goes for when it attacks,” explains Dr. Andrew King from The Royal Veterinary College (RVC), lead author the study, published in Current Biology today.
A protein essential for metabolism and recently associated with neurodegenerative diseases also occurs in several brain-specific forms. This discovery emerged in the course of a research project funded by the Austrian Science Fund FWF, the findings of which have now been published in the journal Human Molecular Genetics. The scientists working on the project discovered a large new region in the genetic code of the protein PGC-1alpha. Previously unknown variations of the protein, which can be found specifically in the brain, are produced from this region. This discovery may provide tissue-specific starting points for the development of new treatments for neurodegenerative diseases like Huntington’s, Parkinson’s and Alzheimer’s.
PGC-1alpha is a real jack-of-all-trades. As a central regulator of metabolic genes that coordinate energy metabolism, the protein, which functions as a “transcriptional coactivator”, influences major body functions. The extent to which the protein also influences medical conditions like obesity, diabetes and metabolic syndrome is unclear, and was under further investigation as part of a research project funded by the Austrian Science Fund FWF. In the course of their research, however, the scientists stumbled on unexpected findings with a particular relevance for neurodegenerative diseases.
Major Difference
A research team headed by Prof. Wolfgang Patsch from the Departments of Pharmacology and Toxicology, and Laboratory Medicine at the Paracelsus Medical University established that the gene which codes for PGC-1alpha (PPARGC1A) is six times larger than hitherto assumed. A new promoter was actually found at some distance (ca. 580 kb) from the previously known gene. A promoter is a DNA segment usually occurring upstream from a gene that can ultimately control how that gene is expressed as a protein. The transmission of genetic information from DNA to RNA molecules, i.e. transcription, is an important intermediate step in this process.
Transcripts, which are produced from the newly discovered promoter, were now examined in detail as part of the research project. “These transcripts differ in important regions from those encoded by the previously characterized - reference - PPARGC1A locus. Based on these differences, we were able to show that these previously unknown transcripts are produced specifically in human brain cells and are at least as common there as the reference transcripts,” explains Dr. Selma M. Soyal, first author of the article currently published in Human Molecular Genetics. Further analyzes showed that the differences in the transcripts lead to the formation of proteins which differ from the protein that acts as a reference, in particular at the N-terminus. Other differences were found within the PGC-1alpha amino acid chain.
When the different PGC-1alpha proteins were localized in human cells (SH-SY5Y), another surprise awaited the scientists: whereas the reference protein was located mainly in the cell nucleus, one of the newly discovered variants was mainly found in the surrounding cytoplasm; another was found both in the nucleus and in the cytoplasm. According to Prof. Patsch: “It is likely that the differences we found in the transcripts influence mechanisms in the finished proteins which control their localization in the cell.”
A Protein With Impact
The detailed functional characterization of the brain-specific proteins could prove significant, as PGC-1alpha is associated with various neurodegenerative diseases such as Huntington’s disease, Parkinson’s and Alzheimer’s - a link that was also confirmed by the project. Using complex statistical analyses, sequence differences in the new promoter were examined in 1.706 Huntington patients as part of a collaboration with the European Huntington’s Disease Network. A clear correlation emerged here between different sequence patterns and the age of onset of the disease in the patients. In addition, the scientists were also able to show that the newly discovered promoter is active in nerve tissue. This indicates that it may actually play an important role in the only partly known links between PGC-1alpha and the neurodegenerative diseases in question.
Overall, the findings of this project, which is funded by the Austrian Science Fund FWF, indicate complex functions of PGC-1alpha in humans. If the scientists succeed in reaching a better understanding of this complexity, PGC-1alpha could provide new possibilities for future therapeutic intervention in key neurodegenerative diseases.