Rare genetic disorder suggests possible cause of neurodevelopmental disorders
Led by Drs Sahin and He, the research team from the FM Kirby Neurobiology Center at Children‘s Hospital Boston (MA, USA), hypothesize that some neurodevelopmental disorders are caused by structural abnormalities in neurons, which could potentially be restored to normal.
Tuberous sclerosis complex (TSC) is a condition that results in benign tumors growing in the brain and other vital organs. Symptoms include seizures, developmental abnormalities, behavioral problems, skin abnormalities, and lung and kidney disease. The disease is caused by mutations of either the TSC1 or TSC2 gene, which encode for proteins that act as tumor growth suppressors. Using mice, the researchers also demonstrated that when these genes are inactivated neurons grow too many axons. Axons are vital for accurate information flow and, according to Dr Sahin, “…if initial polarity is not formed properly, the result will be abnormal connectivity in the brain.”
Approximately half of people with TSC are also autistic and the findings support the idea that the extra axons and subsequent misfiring may be the cause of, or at least a contribution to, autism. Funding from the Autism Speaks, the Manton Foundation and the Tuberous Sclerosis Alliance will allow the team to investigate this idea further.
Another interesting finding is that the team was able to limit the multiple axon formation by administering rapamycin, a cancer drug that suppresses the SAD-A kinase protein. In organisms with inactivated TSC1 and TSC2, SAD-A kinase is produced in excess and is found in large quantity in the abnormally large cells that make up tubers. Not only do these findings suggest that it may be possible to ameliorate the symptoms of epilepsy, mental retardation and autism, but the authors speculate that it may also be possible to manipulate the TSC pathway to regenerate or repair axons lost or damaged in spinal cord or other nerve injuries. Dr Sahin concludes: “these findings provide a potential explanation for neurological abnormalities in TSC patients and perhaps in people without TSC. The challenge remains as to how to treat these conditions. We have some clues but a lot more research needs to be done.”
Source: Choi YJ, Di Nardo A, Kramvis I et al.: Tuberous sclerosis complex proteins control axon formation. Genes and Development 22, 2485–2495 (2008).
Brain tumor differentiation
The study by scientists from the MD Anderson Cancer Center (TX, USA) was presented at the American Association for Cancer Research Molecular Diagnostics in Cancer Therapeutic Development meeting in Philadelphia (PA, USA), held 22–25 September 2008, and analyzed gene expression among patients with glioblastomas. It showed that there are three subgroups of tumors, which differ in the degree of methylation. Patients who had high or low levels of methylation were less likely to survive compared with those who had a mixed level of methylation. In methylation, healthy genes can be switched on or off, which can cause cancer without changing the underlying DNA sequence.
Patients who showed evidence of either extensive or very low levels of methylation had a poor median survival rate of 47–54 weeks following diagnosis. In addition, fewer than 20% of patients in these two subgroups survived for more than 2 years. In contrast, patients in the third subgroup, who had over- or under-methylation of CpG islands, as well as methylation of some genes that were unmethylated in the other subgroups, had a median survival rate of 99 weeks and a 50% chance of living for more than 2 years.
Using the Cancer Genome Atlas, the researchers analyzed data from 183 glioblastoma patients and divided the data to include the CpG islands that showed a high variation among the samples; this resulted in 143 CpG islands and highlighted the three subgroups of tumors. The team of scientists also used 153 patient samples to compare the association between the tumors‘ methylation with their expression of mRNA. A total of 14 of the 51 genes that were specifically methylated in the mixed group showed a related, greater than 1.5-fold decrease in expression, compared with three of the 13 genes specifically methylated in the other two groups.
The researchers found the mRNA gene expression profile of the mixed group significantly differed from the others. This was particularly true in an increased expression of genes whose overexpression had previously been found to be associated with improved outcomes, whereas other genes that have previously been associated with poor outcomes were underexpressed in this group. However, not only did the researcher find that there were more than 200 genes with a higher than 2.5-fold difference in expression between the mixed group versus the other two groups, but they also found that there was minimal gene expression variability between the high and low methylation groups.
Lead author Dr Christopher E Pelloski stated that, “This study shows that the methylation status of CpG islands may serve a robust, and previously unexplored, source of biomarkers for this disease. It also indicates that there seems to be a common theme to glioblastoma that the more closely the tumor cells resemble cells of neural development, the less aggressive the clinical course; whereas if they more resemble mesenchymal cells, which are poorly differentiated and invasive, the worse the clinical outcome will be.”
Source: American Association for Cancer Research www.aacr.org
Boost for Alzheimer‘s disease research
A key question that still requires answering in the puzzle over Alzheimer‘s disease is: what causes the healthy nerve cells to switch off?
Research in this area has been given a boost by the awarding of a UQ Foundation Research Excellence Awards to Dr Elizabeth Coulson of the Queensland Brain Institute, Brisbane, Australia. The Aus$80,000 grant will further Coulson‘s Nerve Cell Survival Laboratory‘s previous work that determined that the p75 neurotrophin receptor was needed for the neurotoxin β-amyloid to cause nerve cell degeneration in the basal forebrain. This work is crucial as at present Alzheimer‘s disease affects approximately 10% of people over 65 years, and 40% of those over 80 years of age, and is an ever increasing problem.
The precise cause of memory loss in Alzheimer patients is not yet understood and may be multifactorial, but work by Coulson and others is beginning to provide some answers. Of the lab‘s success so far, Coulson says: “Discovering how β-amyloid triggers neuronal degeneration has been a question bugging neuroscientists for decades and we have identified an important piece of the puzzle.”
The grant money will go towards helping to understand more about the role of the p75 neurotrophin receptor in cell death and cognitive decline by studying the sortilin family of p75-interacting proteins.
Source: The University of Queensland, Brisbane, Australia www.qbi.uq.edu.au
New prognosis method for comatose patients
It has always been extremely difficult to discern whether a patient in a coma will recover. However, a recent study, which was presented at the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) 55th Annual Meeting in Providence (RI, USA) on 17–20 September 2008, demonstrated the potential of nerve activity in predicting the outcome of nontraumatic comatose patients.
The researchers‘ studied evoked nerve responses to compare nerve activity with the likelihood of survival in 47 nontraumatic comatose adults.
A total of 188 somatosensory evoked potential (SEP) measurements were obtained from the patients within 5 days of them being comatose. The results showed that of the eight patients who had bilateral loss of cortical SEPs, they all died.
Of the remaining 39 patients who showed some signs of nerve activity, only 14 survived. In conclusion, this study proposes that the loss of bilateral nerve response can predict the death of the patient but it is not possible to predict whether the patient will live or die if they have some nerve response.
Researcher Dr Margareth Kai concludes, “There is sufficient evidence for clinicians to use SEPs in the prediction of outcome after brain injury; however, in nontraumatic coma due to various systemic diseases, mainly in children, we must study a larger group of patients to be sure of the accuracy of the study. Systematic multimodal neuromonitoring will help not only to assess the patient‘s prognosis, but also help us to prevent cerebral deterioration, and to evaluate and determine the therapeutic improvement of the intensive care unit patient.”
Source: American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) www.aanem.org