OGDHL, a key protein required for normal function of the mitochondria
- the energy-producing factory of the cell - and its chaperone,
nardilysin (NRD1) are linked to progressive loss of neurological
function in humans, discovered an international team of scientists.
Working with the fruit fly, an experimental animal
model in the lab, the scientists found a mechanism by which
misregulation of mitochondrial function leads to neurodegeneration. The
results appear in Neuron
‘The variants in the genes OGDHL and nardilysin are linked to neurodegenerative disease in humans, revealed a new study.’
"In our research we look for genes whose loss of function results in
deterioration of neurological functions in the fruit fly Drosophila
melanogaster," said first author Dr. Wan Hee Yoon, postdoctoral fellow
in the laboratory of Dr. Hugo Bellen, professor at Baylor College of
Medicine, investigator at the Howard Hughes Medical Institute, and
senior author of the paper. "In the fly we found that loss of function
of nardilysinled to a slow, progressive neurodegeneration."
Yoon and colleagues discovered that nardilysin helps the folding of
an important protein, an enzyme called OGDH, present in mitochondria.
Loss of nardilysin function results in loss of OGDH and a build-up of a
compound called a-ketoglutarate (a-KG). High levels of a-KG increase a
cellular response mechanism called mTOR that normally provides clearance
of cellular components such as proteins and organelles.
that mutation of nardilysin leads to abnormal build-up of a-KG followed
by mTOR activation and eventually to slow accumulation of cellular
trash. Importantly, a drug named rapamycin suppresses the
neurodegenerative conditions caused by this accumulation of cellular
In 2009, a group led by Dr. Eiichiro Nishi in Japan genetically
engineered a mouse to lack nardilysin.The mice developed neurological
problems with motor coordination, balance and memory issues, findings
which at the time were not known to be linked to the mechanism described
above in the fruit fly.
The team led by Bellen realized that the
results in fruit flies and in mice might suggest a role for nardilysin
and its target protein OGDH in neurological problems in humans.
Searching for disease variants of nardilysin, OGDHL
At the same time that Yoon was investigating nardilysinand its
target protein OGDH, across the street co-author Dr. Ender Karaca, a
postdoctoral fellow in the laboratory of Dr. James R. Lupski's group at
Baylor, was working to solve a rare disease by sequencing the patient's
genome through the Baylor-Hopkins Center for Mendelian Genomics (BHCMG).
Karaca had discovered a 16-year-old patient with a rare variant in
OGDHL who was unable to walk, was bound to a wheelchair and whose head
had not grown normally. Yoon and Karaca connected and realized that the
mechanism in flies that Yoon was working on might explain the
undiagnosed patient of Karaca.
"We realized that Ender had identified
OGDHL as the top candidate gene for his patient at the same time that we
were identifying OGDHL as a target of nardilysin," said Yoon. "After we
saw a patient with a severe disorder and variants in OGDHL, we wondered
about nardilysin," said Bellen.
The researchers then widened their
search for similar patients by posting the information of the
disease-causing variants of nardilysinin GeneMatcher, a web tool for
rare disease researchers developed by the BHCMG team at Johns Hopkins
University. Researchers looking for patients carrying rare disease genes
post the gene in GeneMatcher.
If another researcher around the world
has a patient with a matching gene, the teams can contact each other to
share the information and collaborate. By posting nardilysinin
GeneMatcher, Yoon and colleagues identified a patient whose DNA had been
sequenced at the University of California in Los Angeles Clinical
The patient is a 15-year-old boy who presents with
symptoms that are remarkably similar to those present in the patient
identified by Karaca. "We knew then that these two patients had a very
similar disorder, but we had to prove that the genetic variants were
causing their conditions," said Yoon and Bellen.
Using flies to study how human disease genes work
The data from the two patients were strong evidence that the
variants in nardilysin and OGDHL are linked to neurodegenerative disease
in humans. However, to establish that the disease variants can cause
the condition, the researchers turned back to the flies where they could
use genetic technology to test the variants.
"We can test a human gene
side by side with a copy containing a variant from a patient in flies,"
said co-author Dr. Michael F. Wangler, assistant professor of molecular
and human genetics at Baylor. Using this technology, Yoon showed that
mutant flies carrying a normal copy of the human gene show normal
development and neuronal function.
However, flies carrying genes with
deleterious variants found in patients failed to rescue the loss of the
genes in flies. This suggests that the mutations found in patients are
"These studies show how valuable the fruit fly model is to uncover
and test genes linked to human conditions, and to work out how mutations
may cause diseases," said Bellen.