I pay
attention to you guys, you know. I like
to watch how the Top Five posts change over time. The Central Dogma will probably always be
number one since it is so essential to understanding many of the posts on here,
but I find it really interesting that Cancerous Mutational Problems is hanging
strong in the fourth position! I’m even
more amazed that Progeria is number two.
I wrote that post while very sick so I’m glad to see it’s getting so
much love. In fact, I’m so glad that
when I saw a blurb in Nature magazine this week about a new progeria treatment,
I immediately pulled up the paper and decided to write a post about it. Consider this Progeria: Part Two (and you might want
to read up on The Central Dogma while we’re at it…)
. If you’ve read any of my disease posts (HPV,
Sickle Cell Anemia, Influenza), you’ll know that I’m completely fascinated by
understanding diseases at the molecular and cellular level. The patient symptoms are all caused by
problems way down at the atomic level. I
think it’s awesome that scientists can identify one protein, one mutation, one mechanism
of action that can lead to such larger effects.
In Sickle Cell Anemia, a simple DNA base change from A to T is able to
distort the entire structure of hemoglobin, which disrupts the structure of red
blood cells causing them to clump and clog blood vessels leading to pain,
anemia, and inflammation. One small DNA
base change!
Interestingly
enough, progeria is very similar in its cause.
The gene LMNA encodes for the protein lamin A, which is necessary for our
cells’ nuclei to maintain structure. After
the protein is translated at the ribosome, lamin A has a molecule attached to
it that I’m going to call an F group. Many proteins gain F groups and they are
useful for keeping proteins attached to membranes instead of floating off into
the cytoplasm (Figure 4.2). As with anything in cells, a specialized
protein exists to add F groups to proteins; we will call it the FT protein.
After a time, it becomes necessary for lamin A
to remove its F group. Luckily, the very
end of its protein has an area that allows for the F group to be cut off.
The entire process of creating
lamin A is outlined in Figure 77.1.
So what is different about patients
with progeria?
The LMNA gene has one DNA base change, which is also called by
scientists as a point mutation.
At the outset, one probably wouldn’t
think one DNA base change is a big deal.
However, similar to sickle cell anemia, this switch of a base at this
particular point leads to protein that differs in function and localization
within the cell.
The LMNA gene is transcribed with the point mutation and the resulting
protein translated at the ribosome lacks the end necessary for removing an F
group. A lamin A protein unable to
have its F group removed is called progerin. The FT protein comes along, adds the F group
and now progerin is stuck in membranes.
Specifically, progerin builds up at the inner nuclear membrane resulting
in distortion of the nucleus (Figure 4.2). Scientists feel that the progeria symptoms
are based, at least in part, on this build up of progerin at the nuclear
membrane.
The entire process of making
progerin is outlined in Figure 77.2.
So, now what? I told you that many proteins gain F groups,
not merely lamin A/progerin, and one is a particular class of proteins that are
highly involved with cancer called Ras proteins. If Ras proteins can’t gain an F group and
therefore embed themselves in the cellular membrane then they are far less able
to mediate their cancer-causing problems.
For this reason, researchers developed drugs capable of binding to
proteins where an F group would be added and rendering an FT unable to do so. These drugs are called FTIs.
Unfortunately for a variety of reasons, the FTI lonafarib wasn’t an
amazing cancer drug, but scientists wondered if it would be beneficial for
progeria. If the progerin protein can’t
gain the F group then it won’t become stuck in membranes, cluster at the
nuclear membrane, and cause symptoms in its sufferers (Figure
77.3).
And now we’ve come to the
new/re-purposed progeria drug that is being discussed in the news right now:
lonafarnib! I’ll sum up the results
briefly for you here, but if you are curious and want to read more, check out
my newest post on Dr. Amedeo, Progeria Hope!. The
beginning is a bit science-y, but the last few paragraphs discuss the drug’s
ability to improve progeria patients.
Researchers originally showed that
cells expressing progerin that were treated with lonafarnib had nuclei that
returned to normal shape and function.
Mice expressing progerin also displayed improvements from their
progerin-related symptoms. For this
reason, scientists set out to do an initial clinical trial involving 75% of the
worldwide progeria population. After two
years, each child showed improvement in at least one of the following groups:
increased weight gain, improved cardiovascular stiffness, bone structure, and
audiological status. By far and away the
most important gain for those with progeria is the improvement in
cardiovascular health, since ultimately this is what causes death for those
with progeria.
F group: This is actually
called a farnesyl group, but I worried such a chemistry-related word would make
people stop reading! It’s a 15 carbon
molecule that is hydrophobic and used by many proteins to anchor themselves to
membranes (whose
inside are also hydrophobic).
FT protein: This is actually
called a farnesyltransferase.
Point mutation: One DNA
base change from a healthy person’s gene (also called wild type gene among the
scientific community) and a mutated gene.
Progerin: A shortened
form of the protein lamin A that cannot have its F group removed.
FTIs: These are actually
called farnesyltransferase inhibitors.
REFERENCES
Gordon et al. PNAS (2012) 109(41) pgs. 16666 – 16671
Alberts et al. “Molecular Biology of the Cell, 4th
Edition.” Garland Science, New York, New
York. (2002).
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