Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Attacks of King George III’s madness linked to key metabolism molecule

26.08.2005


PGC-1 mediates effects of nutrition on blood disease porphyria



Dana-Farber Cancer Institute researchers say they have uncovered a molecular explanation for the episodic attacks of irrational and demented behavior in porphyria, the disease believed to have afflicted "Mad" King George III, the British ruler blamed for the loss of the American colonies in the Revolutionary War.

The mental and physical symptoms of porphyria, a rare genetic blood disease which a number of modern researchers believe plagued King George intermittently throughout his tumultuous reign, can be brought on by fasting and exposure to certain drugs, and is successfully treated by feedings of sugar and high-carbohydrate food. A biological explanation for these nutritional effects has been lacking.


The Dana-Farber scientists say in a report featured on the cover of the August 26 issue of Cell that the nutritional component of porphyria involves a key master metabolic molecule, PGC-1 alpha, in cells of the liver. The gene that makes PGC-1 alpha was isolated in 1998 in the laboratory of Bruce Spiegelman, PhD, who is senior author of the new report. Postdoctoral fellow Christopher Handschin, PhD, is lead author.

"We’ve explained how porphyria symptoms can occur in episodic attacks triggered by fasting, and why they can be treated by feeding carbohydrates and glucose," says Spiegelman.

King George III suffered from five prolonged, severe episodes of madness during his rule from 1760 to 1820, a period in which he both expanded the British Empire and so stubbornly refused to negotiate with the rebellious American Colonists that they felt only a revolution against England could resolve their grievances. The symptoms recorded at the time sound to modern diagnosticians as typical of porphyria, though the King’s attacks were unusual in their severity and that they didn’t appear until he was 50.

Several types of porphyria exist, all of them stemming from inherited mutations that disrupt the body’s manufacture of heme. A reddish pigment that contains iron, heme is a building block of the oxygen-carrying hemoglobin in red blood cells. The complex synthesis requires eight different enzymes, and when any of them is deficient because of a mutation, the process is blocked. The resulting back up of "precursor" substances is toxic, and can cause a range of symptoms, including dark colored urine, abdominal pain, nausea, vomiting, constipation, weakness in the limbs, and psychiatric symptoms such as confusion, fits and hallucinations.

Earlier this year, the British journal Lancet published a report saying that a test of strands of George III’s hair contained arsenic, which can provoke porphyria attacks. The authors of that report suggested that, ironically, he may have been exposed to arsenic contamination of a substance his doctors gave him as treatment.

PGC-1 alpha is a "transcriptional coactivator" that acts as an on-off switch for a number of genes involved in manufacture of glucose in the liver and in the "heating system" of brown fat cells that help prevent damage from cold in certain animals.

With their intimate knowledge of PGC-1 alpha and its varied roles in energy metabolism, the Dana-Farber researchers wondered if it might be involved in porphyria, since PGC-1 alpha is a regulator of heme manufacture in the liver. One of its actions is controlling the activity of the ALAS-1 gene that makes a protein that’s crucial to the normal manufacture of heme. A defect in this genetic signaling pathway could cause ALAS-1 to accumulate in high levels, leading to the symptoms of porphyria attacks.

"We found that PGC-1 alpha is an important factor controlling the expression of ALAS-1 in the fasted and fed liver," the authors write. "Moreover, we showed that hepatic [in the liver] PCG-1 alpha is a major determinant of the severity of acute porphyric attacks in mouse models of chemical porphyria."

Through a series of experiments with normal mice and those engineered to lack the PGC-1 alpha gene, the researchers said they have provided "a clear-cut mechanism" linking fasting to an increase in PGC-1 alpha, and, in turn, overactivity of the ALAS-1 gene. The therapeutic effect of glucose and high-carbohydrate diets on porphyria, they add, occurs because glucose causes the pancreas to make more insulin, which results in suppression of the PGC-1 alpha gene.

The findings suggest that patients with porphyria should avoid any drugs or foods that turn on PGC-1 alpha activity in the liver, the researchers say. There could be implications for treatment as well: high-carbohydrate diets aren’t a satisfactory therapy for affected patients as it make them gain, and fasting in order to lose the weight risks provoking attacks. Hopefully, the researchers say, it might be possible to develop more specific treatments now that the mechanism underlying the symptoms of porphyria is better understood.

Bill Schaller | EurekAlert!
Further information:
http://www.dfci.harvard.edu
http://www.dana-farber.org

More articles from Life Sciences:

nachricht Newly designed molecule binds nitrogen
23.02.2018 | Julius-Maximilians-Universität Würzburg

nachricht Atomic Design by Water
23.02.2018 | Max-Planck-Institut für Eisenforschung GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Attoseconds break into atomic interior

A newly developed laser technology has enabled physicists in the Laboratory for Attosecond Physics (jointly run by LMU Munich and the Max Planck Institute of Quantum Optics) to generate attosecond bursts of high-energy photons of unprecedented intensity. This has made it possible to observe the interaction of multiple photons in a single such pulse with electrons in the inner orbital shell of an atom.

In order to observe the ultrafast electron motion in the inner shells of atoms with short light pulses, the pulses must not only be ultrashort, but very...

Im Focus: Good vibrations feel the force

A group of researchers led by Andrea Cavalleri at the Max Planck Institute for Structure and Dynamics of Matter (MPSD) in Hamburg has demonstrated a new method enabling precise measurements of the interatomic forces that hold crystalline solids together. The paper Probing the Interatomic Potential of Solids by Strong-Field Nonlinear Phononics, published online in Nature, explains how a terahertz-frequency laser pulse can drive very large deformations of the crystal.

By measuring the highly unusual atomic trajectories under extreme electromagnetic transients, the MPSD group could reconstruct how rigid the atomic bonds are...

Im Focus: Developing reliable quantum computers

International research team makes important step on the path to solving certification problems

Quantum computers may one day solve algorithmic problems which even the biggest supercomputers today can’t manage. But how do you test a quantum computer to...

Im Focus: In best circles: First integrated circuit from self-assembled polymer

For the first time, a team of researchers at the Max-Planck Institute (MPI) for Polymer Research in Mainz, Germany, has succeeded in making an integrated circuit (IC) from just a monolayer of a semiconducting polymer via a bottom-up, self-assembly approach.

In the self-assembly process, the semiconducting polymer arranges itself into an ordered monolayer in a transistor. The transistors are binary switches used...

Im Focus: Demonstration of a single molecule piezoelectric effect

Breakthrough provides a new concept of the design of molecular motors, sensors and electricity generators at nanoscale

Researchers from the Institute of Organic Chemistry and Biochemistry of the CAS (IOCB Prague), Institute of Physics of the CAS (IP CAS) and Palacký University...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

2nd International Conference on High Temperature Shape Memory Alloys (HTSMAs)

15.02.2018 | Event News

Aachen DC Grid Summit 2018

13.02.2018 | Event News

How Global Climate Policy Can Learn from the Energy Transition

12.02.2018 | Event News

 
Latest News

Basque researchers turn light upside down

23.02.2018 | Physics and Astronomy

Finnish research group discovers a new immune system regulator

23.02.2018 | Health and Medicine

Attoseconds break into atomic interior

23.02.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>