December 01, 1999
Understanding Key Protein in Fragile X Syndrome
Fragile X syndrome, the most common inherited form of mental
retardation, results from a mutation that affects how genetic messages
are ferried from the cell's nucleus to its protein manufacturing
apparatus. The identification of three new molecules integral to the
protein shuttling process has researchers bearing down on the cellular
mechanisms that underlie fragile X syndrome, and perhaps other causes
of mental retardation as well.
For a condition with such a delicate-sounding name, fragile X
syndrome can cause a number of powerful effects, ranging from learning
disability and hyperactivity to severe mental retardation. Mutations in
the FMR1 gene produce the disorder, and Stephen Warren, a Howard
Hughes Medical Institute (HHMI) investigator at Emory University, has
been studying this gene and the protein it produces, called FMRP, since
he and his colleagues first identified them in 1991.
"When we first identified FMRP, it didn't look like any other
protein that had been identified, so we really didn't know what it did.
But by slowly chipping away over the years, we and others have learned
a lot about it," said Warren.
For example, Warren's group has determined that FMRP binds to
messenger RNA (mRNA) molecules and forms a complex called a RNP
(ribonucleoprotein particle). They also know that FMRP shuttles between
the cell's nucleus and cytoplasm, visiting ribosomes, where the genetic
code for building proteins is translated. This evidence suggested to
Warren and his colleagues that FMRP is somehow involved in the
translation process.
To understand more about FMRP's function in the cell, Warren's group
needed to identify the protein's partners in the RNP complex, a feat
that had defied conventional protein-purifying techniques. Not to be
thwarted, the researchers developed a set of antibodies that allowed
them to isolate not only FMRP, but also messenger RNA (mRNA) and at
least six other proteins from the complex. Warren, together with
colleagues Stephanie Ceman and Victoria Brown, published these results
in the December 1999 issue of the journal Molecular and Cellular
Biology.
With these components in hand, the three researchers proceeded to
identify three of the proteins in the complex. Two of the proteins,
FXR1P and FXR2P, belong to the same family of proteins as FMRP.
A surprise awaited the HHMI team when it identified the third
protein as nucleolin, a protein that scientists thought stays tucked
away in the nucleus. Placing nucleolin in the RNP complex suggests that
it wanders out to the cytoplasm and may help regulate translation.
Since the Molecular and Cellular Biology paper went to press,
Warren's group has tentatively identified additional, more interesting,
proteins in the RNP complex. One is similar to a yeast protein that
helps unwind mRNA during translation. Because translation is known to
be governed in part by changes in mRNA structure, this protein may also
play an important role in regulating the process.
Identifying the proteins in the RNP complex is important, said
Warren, because they may be involved in other types of mental
retardation. "For most forms of mental retardation in humans, the genes
have not been identified. Now that we're identifying some of these
proteins, the next step will be to start screening patients to see if
they have the associated genes."
Warren's group is also starting to study the mRNA from the RNP
complex. "Isolating the RNA that's specifically interacting with the
FMRP will give us a handle on the biggest question in this whole area
of research— what are the messages that are bound to it," said
Warren, who expects to identify most of the messages that bind to FMRP
within the next year. With the messages in hand, the researchers may
finally get a handle on how mutant FMRP— the root molecular cause
of fragile X syndrome— causes mental retardation.
Initially, Warren's group isolated the proteins from cultured
connective tissue cells. While people with fragile X syndrome sometimes
have connective tissue abnormalities, their mental deficits are the
greatest concern, so an obvious question is whether the same proteins
are found in the brain. By modifying their technique, the researchers
were also able to isolate FMRP and the other proteins from mouse
brains.
"Now we've begun to identify the messages from the brain," said
Warren, "and doing that should give us substantial new insights into
the syndrome."
|
