May 25, 2001
Vitamin Deficiency May Worsen Motor Neuron Disease
In
the process of discovering a function for a common modification of proteins in
“Insufficiency of folate and B12 in SMA patients is a real possibility and this could lead to under-methylation of proteins, even if only slightly. Given this possibility, it would seem prudent for these patients, in consultation with their physicians, to ensure that their diet includes the recommended daily requirement of these vitamins.”
Gideon Dreyfuss
the cell, researchers have found evidence that suggests that insufficient amounts
of folic acid and vitamin B12 in the diet may exacerbate spinal muscular
atrophy (SMA), a genetic disease that attacks motor neurons.
The scientists are planning to collaborate with
clinicians to explore whether these vitamins might ameliorate the severity of
symptoms in some SMA patients.
In a research article published in the May 2001 issue
of the journal
Molecular Cell
,
Howard Hughes Medical Institute investigator
Gideon Dreyfuss
and colleagues at the University of Pennsylvania School of Medicine report new
information about how the protein, "survival of motor neurons" (SMN), which is
reduced or defective in people with SMA, attaches to other proteins with which
it interacts.
"SMN is a sort of master builder or chaperone that
helps assemble many large RNA-protein machines (RNPs) in the cell," said
Dreyfuss. "In particular, it appears to help construct complicated molecular
machines that are critical for the production of messenger RNA." Messenger RNA
plays an essential role in ensuring that the information contained in DNA is
properly translated into functional proteins.
SMA is the most common genetic cause of infant
mortality, affecting about one in 6,000 newborns. The disease causes
progressive muscle weakness, wasting, or atrophy as motor neurons degenerate.
The severity of the disease ranges from milder forms, in which people can live
into adulthood, to more severe forms that cause death a few months after birth.
SMA is caused by deletions of one of the two genes
that code for the SMN protein. Deletion of the gene reduces the level of SMN
protein, which causes damage to the nerve cells that serve major muscle groups.
Loss of nerve stimulation causes muscles to atrophy and can result paralysis.
In their studies, Dreyfuss and his colleagues probed
how SMN binds to its multiple target proteins in the cell. Using biochemical
methods, they determined that SMN binds to regions of target proteins that are
rich in the amino acids arginine and glycine. "When we tested binding of SMN to
these proteins directly
in vitro
,
however, we found a surprisingly low affinity," said Dreyfuss. "We then began
to suspect that something else must influence the binding, because when we
isolated the target proteins from cells, SMN bound to them avidly."
To solve the mystery, Dreyfuss and his colleagues used
the long-known fact that the arginines contained in many proteins are modified
by the attachment of two molecules called methyl groups. "Dimethylation of
arginines is a fairly common modification of proteins, especially RNA-binding
proteins, that had first been reported more than thirty years ago," said
Dreyfuss. "But the function of that modification was not known."
By using synthetic peptides with (or without) the
methylated arginines as found in the cell, the researchers established that SMN
did, indeed, bind tightly to its target proteins only when the arginines on
those target proteins were dimethylated. "That alteration makes the modified
protein interact with another protein — in this particular case with SMN —
with much higher avidity," Dreyfuss said. The alteration of the arginines quite
likely changes the shape of the protein's surface, making it fit SMN more
snugly, he explained.
The finding — which solves a three-decade-old
scientific mystery — provides a new research pathway for studying how proteins
attach to one another and might also have clinical implications for people who
have SMA, said Dreyfuss.
"These SMN target proteins obtain their methyl groups
from a methyl donor called,
S
-adensylmethionine, which itself depends on folate
and vitamin B12 as part of its metabolic pathway," said Dreyfuss. Humans cannot
produce or store folate and B12, so they must obtain those vitamins through their
diet. "The thought is that SMA patients, who are already compromised in their
levels of SMN, might be more severely affected if they are also suboptimal in
their levels of protein methylation," said Dreyfuss.
"Insufficiency of folate and B12 in SMA patients is a
real possibility and this could lead to under-methylation of proteins, even if
only slightly," he said. "Given this possibility, it would seem prudent for
these patients, in consultation with their physicians, to ensure that their
diet includes the recommended daily requirement of these vitamins."
Dreyfuss is planning to collaborate with neurologists
Thomas Crawford of The Johns Hopkins University School of Medicine and Richard
Finkel of The Children's Hospital of Philadelphia to explore whether vitamin
therapy might offer some relief to people with SMA.
Dreyfuss and his colleagues will also continue their
studies of arginine methylation. They plan to begin looking for the enzyme that
catalyzes attachment of methyl groups to the protein targets of SMN. Those
studies, he said, could help reveal the regulatory pathway in a key cellular
process that may extend to other proteins and other degenerative diseases of
the nervous system.
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