Posts tagged microcephaly
Articles and news from the latest research reports.
Impaired cell division leads to neuronal disorder
Prof. Erich Nigg and his research group at the Biozentrum of the University of Basel have discovered an amino acid signal essential for error-free cell division. This signal regulates the number of centrosomes in the cell, and its absence results in the development of pathologically altered cells. Remarkably, such altered cells are found in people with a neurodevelopmental disorder, called autosomal recessive primary microcephaly. The results of these investigations have been published in the current issue of the US journal “Current Biology”.
Cell division is the basis of all life. Of central importance is the error-free segregation of genetic material, the chromosomes. A flawless division process is a prerequisite for the development of healthy, new cells, whilst errors in cell division can cause illnesses such as cancer. The centrosome, a tiny cell organelle, plays a decisive role in this process.
Prof. Erich Nigg’s research group at the Biozentrum of the University of Basel has investigated an important step in cell division: the duplication of the centrosome and its role in the correct segregation of the chromosomes into two daughter cells. The protein STIL has an essential function in this process. It ensures that centrosome duplicate before one half of the genetic material is transported into each of the two daughter cells.
KEN-Box important for protein breakdown
During cell division, the protein STIL is degraded. If this does not occur, the protein accumulates in the cell, which then causes an overproduction of centrosomes. As a consequence, mis-segregated chromosomes are incorporated into the daughter cells, which then represent cells with faulty genetic material. The scientists discovered an amino acid signal on the STIL protein, a so-called KEN-Box, and showed that this is critical for the breakdown of the protein: “The Ken-Box is the signal that orders the protein degradation machinery to break down the STIL protein,” explains Christian Arquint, the first author of this publication. In the absence of the KEN-Box, the protein is not degraded.
Absence of the KEN-Box causes microcephaly
In some patients with microcephaly, a neuronal disorder that leads to a reduced number of nerve cells being produced and, therefore, a smaller brain, the KEN-box is lacking from the STIL protein. The scientists were thus able to demonstrate a tantalizing connection between the absence of this particular amino acid signal and an illness. “When during our investigations of cell division and centrosome duplication we came across a connection to the disorder microcephaly, we were particularly pleased, as this helps us to better understand how this disorder develops“, says Christian Arquint.
In the future, the research group led by Erich Nigg plans to uncover other connections between errors of cell division and the illness microcephaly. They also want to focus on the investigation of other proteins that play important roles in the process of cell division, in particular those involved in centrosome duplication.
One More Homo Species?
A recent 3D-comparative analysis confirms the status of Homo floresiensis as a fossil human species
Ever since the discovery of the remains in 2003, scientists have been debating whether Homo floresiensis represents a distinct Homo species, possibly originating from a dwarfed island Homo erectus population, or a pathological modern human. The small size of its brain has been argued to result from a number of diseases, most importantly from the condition known as microcephaly.
Based on the analysis of 3-D landmark data from skull surfaces, scientists from Stony Brook University New York, the Senckenberg Center for Human Evolution and Palaeoenvironment, Eberhard-Karls Universität Tübingen, and the University of Minnesota provide compelling support for the hypothesis that Homo floresiensis was a distinct Homo species.
The study, titled “Homo floresiensis contextualized: a geometric morphometric comparative analysis of fossil and pathological human samples,” is published in the July 10 edition of PLOS ONE.
The ancestry of the Homo floresiensis remains is much disputed.
The critical questions are: Did it represent an extinct hominin species? Could it be a Homo erectus population, whose small stature was caused by island dwarfism?
Or, did the LB1 skull belong to a modern human with a disorder that resulted in an abnormally small brain and skull? Proposed possible explanations include microcephaly, Laron Syndrome or endemic hypothyroidism (“cretinism”).
The scientists applied the powerful methods of 3-D geometric morphometrics to compare the shape of the LB1 cranium (the skull minus the lower jaw) to many fossil humans, as well as a large sample of modern human crania suffering from microcephaly and other pathological conditions. Geometric morphometrics methods use 3D coordinates of cranial surface anatomical landmarks, computer imaging, and statistics to achieve a detailed analysis of shape.
This was the most comprehensive study to date to simultaneously evaluate the two competing hypotheses about the status of Homo floresiensis.
The study found that the LB1 cranium shows greater affinities to the fossil human sample than it does to pathological modern humans. Although some superficial similarities were found between fossil, LB1, and pathological modern human crania, additional features linked LB1exclusively with fossil Homo. The team could therefore refute the hypothesis of pathology.
“Our findings provide the most comprehensive evidence to date linking the Homo floresiensis skull with extinct fossil human species rather than with pathological modern humans. Our study therefore refutes the hypothesis that this specimen represents a modern human with a pathological condition, such as microcephaly,” stated the scientists.
(Source: commcgi.cc.stonybrook.edu)
A Key Gene for Brain Development
About one in ten thousand babies is born with an abnormally small head. The cause for this disorder – which is known as microcephaly – is a defect in the develoment of the embryonic brain. Children with microcephaly are severely retarded and their life expectancy is low. Certain cases of autism and schizophrenia are also associated with the dysregulation of brain size.
The causes underlying impaired brain development can be environmental stress (such as alcohol abuse or radiation) or viral infections (such as rubella) during pregnancy. In many cases, however, a mutant gene causes the problem.
David Keays, a group leader at the IMP, has now found a new gene which is responsible for Microcephaly. Together with his PhD-student Martin Breuss, he was able to identify TUBB5 as the culprit. The gene is responsible for making tubulins, the building blocks of the cell’s internal skeleton. Whenever a cell moves or divides, it relies on guidance from this internal structure, acting like a scaffold.
The IMP-researchers, together with collaborators at Monash University (Victoria, Australia), were able to interfere with the function of the TUBB5 in the brains of unborn mice. This led to massive disturbances in the stem cell population and impaired the migration of nerve cells. Both, the generation of large numbers of neurons from the stem cell reservoir and their correct positioning in the cortex, are essential for the development of the mammalian brain.
To determine whether the findings are also relevant in humans, David Keays collaborates with clinicians from the Paris-Sorbonne University. The French team led by Jamel Chelly, examined 120 patients with pathological brain structures and severe disabilities. Three of the children were found to have a mutated TUBB5-gene.
This information will prove vital to doctors treating children with brain disease. It will allow the development of new genetic tests which will form the basis of genetic counseling, helping parents plan for the future. By understanding how different genes cause brain disorders, it is hoped that one day scientists will be able to create new drugs and therapies to treat them.
The new findings by the IMP-researchers are published in the current issue of the journal “Cell Reports”. For David Keays, understanding the function of TUBB5 is the key to understanding brain development. “Our project shows how research in the lab can help improve lives in the clinic”, he adds.
The paper “Mutations in the β-tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities” is published on December 13, 2012, in the online Journal Cell Reports.