UNC Science Short: How to Battle Protein Clumping in ALS

November 14, 2019

TDP-43 has been known for about 10 years to
be the major disease protein present in patients with ALS or Lou Gehrig’s Disease. Normally, TDP-43 is a nuclear protein that
ensures proper health and survival of neurons. But for reasons that are currently not clear,
it leaves the nucleus and ends up in the cell’s cytoplasm where it is associated with disease
states. So once TDP-43 is in the cytoplasm, it begins
clumping. The field generally considers these clumps
as a disease hallmark and that reversing the clumping process would be considered a potential
therapy. And so what we’ve found was that we could
reverse these clumps by engineering proteins to grab these TDP-43 clumps and physically
pull them apart. So not only can these proteins pull them apart,
but they can also prevent them from clumping in the first place. We chose to study TDP-43 in skeletal muscle
for two reasons: The first reason is that we have all the tools to study skeletal muscle
and it’s very easy to manipulate skeletal muscle. And the other reason is that TDP-43 is implicated
in a series of other diseases, including inclusion body myositis. Now that we’ve shown this in muscle cells,
we’re hopeful that we can demonstrate this in neurons that would reflect what’s happening
in ALS patients. Our work is very promising and exciting, although
much more work needs to be done to analyze what makes TDP-43 clump in ALS patients as
possible therapies. While our work is very exciting, much more
work needs to be done to generate therapies for patients with ALS. I know our work is very promising, but a lot
of work needs to be done in order to… I know our work is very promising, but a lot
of work needs to be done in order to treat patients with ALS.

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