Molecular trigger for Huntingtons disease found
Researchers have discovered a key regulatory molecule whose overactivation by the abnormal protein produced in Huntingtons disease (HD) causes the central pathologies of the disease. The abnormal HD protein activates the regulatory protein called p53, which in turn switches on a host of other genes. This abnormal gene activation damages the cells power plants, called the mitochondria, and kills brain cells.
The researchers also speculated that disturbances in p53 may also play a role in some forms of Parkinsons disease and amyotrophic lateral sclerosis, or Lou Gehrigs disease.
Ironically, p53 is the same regulatory protein that is inactivated in a large fraction of cancers. This inactivation allows abnormal cancer cells to escape the cells protective "suicide program" that would normally kill them. The researchers theorize that the lower incidence of cancer in HD patients could be caused by the protective effect of overactive p53.
In the July 7, 2005, issue of Neuron, Akira Sawa and colleagues at Johns Hopkins University School of Medicine reported experiments ranging from molecular studies in cultured brain cells to analysis of the brains of human HD patients that demonstrated the central role of p53 in the pathologies of HD.
Their studies with cell cultures showed that the abnormal HD protein selectively binds to p53 and increases its level in cells. They noted that the brains of patients with HD also show substantial increases in the p53 protein, with the highest levels in cases with the most extensive pathology.
The researchers experiments also revealed that this p53 increase causes an overactivation in the genes regulated by p53, which is called a "nuclear transcription factor" because it regulates the transcription of its target genes in cell nuclei.
In studies of cell cultures and of mice engineered to have HD, the researchers found that the p53 increase causes malfunctions in mitochondria. Whats more, they found that this p53 increase induced by the abnormal HD protein greatly increases cell death.
The researchers also found effects of the abnormality in p53 in whole animals. They found that deleting p53 suppresses damage to neurons in the eye of fruit flies engineered to have the abnormal HD protein. And in mice with the abnormal protein, knocking out p53 corrects behavioral abnormalities that the mice otherwise display. These behaviors include abnormal reflexes such as an inhibited startle response to loud noise, which is also present in human HD patients.
"In summary, our study establishes a specific role for p53 in HD," concluded Sawa and colleagues. "As p53 is a nuclear transcription factor that regulates various mitochondrial genes and insofar as mitochondrial dysfunction appears important in HD, our findings provide a molecular mechanism linking disturbances of nuclei and mitochondria in HD." Download PDF
Heidi Hardman | EurekAlert!
The most recent press releases about innovation >>>
Die letzten 5 Focus-News des innovations-reports im Überblick:
Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.
As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...
Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.
Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...
For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.
While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...
An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.
The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...
A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.
Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...