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.
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