Technology Reveals ‘Lock And Key’ Protein ‘behind Alzheimer’s fits’

By Live Dr - Sat Mar 28, 1:20 pm

Protein ‘behind Alzheimer’s fits’

Brain plaque

Brain plaques are a hallmark of Alzheimer’s disease

Scientists in Scotland say they may have found what causes some Alzheimer’s patients to develop epilepsy.

The amyloid protein, which forms in clumps in patients’ brains, makes nerve cells too sensitive and prone to seizures, tests in mice suggest.

The cells short-circuit and fire too many electrical signals, the Journal of Neuroscience reports.

If true in humans too, which the experts say is likely, it may mean some patients will need different drugs.

A mainstay of treatment for Alzheimer’s is a class of drugs called the cholinesterase inhibitors.

They work by stopping the breakdown of acetylcholine, an important neurotransmitter associated with memory.

Our findings could lead to a rethink of the type of drugs that are given to patients with Alzheimer’s disease
Researcher Professor Tibor Harkany

But an unwanted effect is that this can also increase a person’s susceptibility to seizures.

However, medication to control seizures can also make Alzheimer’s symptoms worse.

A third of Alzheimer’s patients have some degree of epilepsy, posing a treatment dilemma for doctors.

New understanding

Researcher Professor Tibor Harkany, of the University of Aberdeen, said he hoped his findings would lead to the discovery of new drugs to treat both problems with fewer side-effects.

He said: “We have shown for the first time the actual cellular process that links epilepsy and Alzheimer’s disease.

“This provides us with a new wave of understanding in Alzheimer’s disease.

“Our findings could lead to a rethink of the type of drugs that are given to patients with Alzheimer’s disease.

“It should be possible to design drugs to tackle the two problems of seizures and cognition at the cellular level because both share common mechanisms.”

Rebecca Wood, chief executive of the Alzheimer’s Research Trust, said: “One third of Alzheimer’s patients have some degree of epilepsy, and some people who live with the disease are 80 times more likely to suffer seizures than the general population.

“This research builds greatly on our understanding of the connection between the two conditions.”

Neil Hunt, of the Alzheimer’s Society, said: “These seizures can be extremely distressing for people with dementia and their families.

“This research enhances our understanding of the relationship between epilepsy and dementia.”

Technology Reveals ‘Lock And Key’ Proteins Behind


Positive match: The “iMYTH-system” showing a positive readout. If two proteins interact in the iMYTH system the yeast cell will stain blue. (Credit: Staglar lab)

ScienceDaily (Apr. 12, 2007) — A new technology developed at the University of Toronto is revealing biochemical processes responsible for diseases such as cystic fibrosis and could one day pave the way for pharmaceutical applications.

A study appearing in the April 13 issue of Molecular Cell describes how U of T and Johns Hopkins University researchers designed a device to test for proteins that play an important role in human health and disease. The technology, iMYTH (or integrated membrane yeast-two hybrid system), scans cells to detect proteins that interact with key proteins called ATP-binding cassette (ABC) transporters — proteins that, when impaired, can cause disease.

One of the best known ABC transporters is the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which, when disabled by mutation, causes cystic fibrosis, a hereditary disease that results in progressive disability and early death. Another important ABC protein is the Multidrug Resistance Protein (MRP), which normally removes drug metabolites and toxins from cells in our bodies but when overzealous can contribute to the drug resistance of tumours, thereby thwarting chemotherapy.

“All the cells in our bodies contain transporters that are poised in cellular membranes and act as ‘gatekeepers’ to allow the entry of certain substances, like nutrients, into the cell and promote the export of other substances, like toxins, out of the cell,” says Professor Igor Stagljar, Department of Medical Genetics and Department of Biochemistry at the University of Toronto and lead author of the study. “When the function of these transporters is impaired, disease can result. This device gives us insights as to what proteins are interfering with this process.”

iMYTH works by scanning cells to reveal proteins that fit with the transporters, the only screening system sophisticated enough to work with delicate membrane proteins. Simply, if two proteins interact in iMYTH, they will stain the yeast cell blue. “Like lock and key, if two proteins interact with one another, it is safe to assume they participate or regulate the same cellular process,” explains Stagljar. “Identifying new interactors for ABC transporters may reveal unanticipated aspects of how these transporters function and help researchers gain clues for fighting disease and drug resistance.”

Using iMYTH, the Stagljar lab identified six proteins that interact with and presumably communicate with the ABC transporter Ycf1p, a yeast version of the human proteins CFTR and MRP. These newly discovered protein interactors represent novel potential pharmaceutical targets. Through a series of biochemical and genetic tests, the researchers discovered that one of these interactors, Tus1p, regulates Ycf1p transporter function in a completely novel way to stimulate its ability to remove toxins from the cell.

“The more we learn about membrane proteins, the better we can use this knowledge for pharmacological and clinical applications,” Stagljar says. “We work by putting together biochemical processes piece by piece like a puzzle. Hopefully soon we will have a complete picture of how many other diseases such as breast cancer, heart diseases, arthritis and schizophrenia are caused by mutations in various human membrane proteins.”

The study was funded by the Canadian Institute of Health Research (CIHR) and Gebert Ruf Foundation from Switzerland.

Adapted from materials provided by University of Toronto, via EurekAlert!, a service of AAAS.


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