BIOCHEMISTS SOLVE ADDRESS PROBLEM IN CELLS THAT LEADS TO LETHAL KIDNEY DISEASE

Research by UCLA biochemists may lead to a new treatment -- or even a cure -- for PH1, a rare and potentially deadly genetic kidney disease that afflicts children. Their findings also may provide important insights into treatments for Parkinson's disease, Alzheimer's disease and other degenerative diseases.

Led by Carla Koehler, a professor of chemistry and biochemistry in the UCLA College, the researchers identified a compound called dequalinium chloride, or DECA, that can prevent a metabolic enzyme from going to the wrong location within a cell. Ensuring that the enzyme -- called alanine: glyoxylate aminotransferase, or AGT -- goes to the proper "address" in the cell prevents PH1.

The findings were published online in the Proceedings of the National Academy of Sciences and will appear later in the journal's print edition.

In humans, AGT is supposed to go to an organelle inside the cell called the peroxisome, but for people with a particular genetic mutation, the enzyme mistakenly goes instead to the mitochondria -- tiny power generators in cells that burn food and produce most of the cells' energy -- which causes PH1.

Koehler's team demonstrated that adding small amounts of DECA, which is FDA-approved, to cells in a Petri dish prevents AGT from going to the mitochondria and sends it to its proper destination, the peroxisome.

"In many mutations that cause diseases, the enzyme doesn't work," Koehler said. "In PH1 the enzyme does work, but it goes to the wrong part of the cell. We wanted to use DECA in a cell model to block AGT from going to the wrong address and send it back to the right address. DECA blocks the mitochondria 'mailbox' and takes it to the peroxisome address instead."

How often did it work?

"All the time," said Koehler, a member of UCLA's Jonsson Comprehensive Cancer Center, Molecular Biology Institute and Brain Research Institute.

For people with the mutation, the correct peroxisome address is present in AGT, but it is ignored because it is accompanied by the address of the mitochondria, which the cell reads first, Koehler said.

Koehler, who also is a member of the scientific and medical advisory board of the United Mitochondrial Disease Foundation, hopes to find out whether a similar "correct address" strategy can slow cancer down. Her laboratory has identified approximately 100 other small molecules, which she calls MitoBloCKs, that she and her colleagues are testing for their ability to combat Parkinson's, Alzheimer's and other diseases.

PH1 -- short for primary hyperoxaluria 1 -- starts at birth and is usually fatal for patients who do not receive both kidney and liver transplants. Approximately half of those with the disease have kidney failure by age 15. Koehler has presented her findings to the Oxalosis and Hyperoxaluria Foundation, which provides support for PH1 patients and their families.

Scientists' ability to diagnose rare diseases has improved in recent years because technological advances in genomics have made it easier to identify more genetic mutations, Koehler said.

According to Koehler, to treat diseases, scientists must first understand how proteins like AGT move inside the cell. Her research, which encompasses biochemistry, genetics and cell biology, studies how mitochondria are assembled and function, how proteins enter the mitochondria and reach the right location inside cells, and how mitochondria communicate with the rest of the cell.

Her laboratory uses model systems that enable them to study the biochemistry in a way that is not possible with humans. Much of the work is conducted in yeast.

"It's exciting that our studies in baker's yeast, a typical laboratory model, might be able to help kids with a complicated disease," Koehler said.

GENETICISTS SOLVE 40 YEAR OLD DILEMMA TO EXPLAIN WHY DUPLICATE GENES REMAIN IN THE GENOME

Geneticists at Trinity College Dublin have made a major breakthrough with important implications for understanding the evolution of genomes in a variety of organisms.

They found a mechanism sought for more than four decades that explains how gene duplication leads to novel functions in individuals.

Gene duplication is a biological phenomenon that leads to the sudden emergence of new genetic material. 'Sister' genes -- the products of gene duplication -- can survive across long evolutionary timescales, and allow organisms to tolerate otherwise lethal mutations.

The Trinity geneticists have now identified and described the mechanism underlying this increased tolerance, which is known as 'mutational robustness'.

By experimentally demonstrating that this robustness is important for yeast cells to adapt to novel conditions, including those that are stressful to the cells, they have underlined the likely reason for the existence of gene duplication.

"Natural selection -- a process that keeps essential things in the cell -- also removes genes that are redundant from the genome," said Dr Mario A Fares, Assistant Professor in Genetics at Trinity, and leading author of the study.

"The mechanism resolving the conflict between sister genes and their apparent evolutionary instability had remained a mystery for decades, but we have now cracked this latest part of the genetic code."

Gene duplication is a frequent phenomenon in eukaryotic organisms (which safeguard their genetic material within cell membranes), including yeast, plants, and animals. But understanding how duplication leads to biological innovation is difficult because evolution cannot be easily traced seeing as it occurs on timescales in the order of millions of years.

Despite their apparently redundant nature, duplicate genes that originated 100 million years ago can still be found in today's organisms. This phenomenon has always suggested the existence of a mechanism maintaining them in the genomes. The researchers in this study chose to work with yeast -- an organism whose entire genome has been duplicated over time -- to join up the dots.

They 'evolved' yeast cells in the laboratory under conditions that allowed the spread of mutations rejected by natural selection, by simply reducing the effect that natural selection had on these 'maladapted' cells. They found that duplicate genes tolerated the maladaptive mutations to a greater degree than non-duplicate genes.

The geneticists' simple experimental approach revealed that these genes, duplicated 100 million years ago, were still able to respond to different environments as they changed, as well as highlighting their potential to generate new adaptations that might give them an advantage in new environments.

"Discovering the mechanism of innovation through gene duplication marks an exciting beginning for a new era of research in which evolution can be conducted in the laboratory and theories hitherto speculative tested," added Dr Fares.

"Our discovery also has implications for explaining the importance of redundancy in the human society as well. The role of increased redundancies in a fashioned job market in lenient economical conditions could lead, in crisis times, to the emergence of new companies, specialized workforces, and the optimization of individual capabilities, for example, although this requires a profound investigation."

The research, recently published online in the international journal, Genome Research, was supported by Science Foundation Ireland (SFI).