>> This observation was built on our initial studies
in trying to understand a very common version of ALS
and dementia associated
with a mutation called C9orf72 which we'll call C9
for the sake of simplicity, it's easier to say.
And that mutation which is found in ALS
and frontal temporal dementia, accounts for about 40%
of the familial form of the disease
and actually about almost 10% of the sporadic form.
Back in 2015 my colleague in that study
and in the current study, Tom Lloyd and I had tried
to understand what was the nature of the defect.
How does that mutation cause, initiate disease?
So with the help of Tom Lloyd and fly models that he had
that were based on this mutation and previous work
by my ex-postdoc Chris Donnelly, we ended up discovering
that nuclear transport was the fundamental defect
in this C9 mutation.
Nuclear transport, every cell obviously has DNA
in the nucleus.
DNA is coded for messenger RNA and messenger RNA leaves
the nucleus but there are a lot
of processes that are important.
So I just said the messenger RNA leaves the nucleus.
Well this is a very regulated process.
And every nucleus has something known
as the nuclear pore complex.
It's up to 500 proteins that make up
this cylindrical like object
and there are about 2000 nuclear pore complexes
per mammalian cell.
And each nuclear pore complex is made up
of individual proteins known as nucleoporins.
This is important to our current study.
So this beautifully organized structure essentially
regulates what gets in and out of the nucleus.
The nucleus needs material to operate, new proteins.
That comes from the nuclear pore.
The nucleus releases RNAs in many cases
to the cytoplasm to make future proteins and translation.
All of that is regulated by the nuclear pore.
So it's clear that defects in nuclear transport
are being seen now in multiple diseases.
We and actually others have shown that this occurs in ALS.
It occurs in Huntington's disease and nuclear transport
is essential for the cell.
One reason why this cellular process appears to be defective
is because of the formation of stress granules
and their sequestration of nuclear pore proteins.
One of the things we don't know is, nuclear pore proteins
once they form this complex,
these NPCs, nuclear pore complexes.
How often do those proteins
that make it up come on, come off
or are they just fully stable?
We know from other experiments,
yeah they're not fully stable.
There's a real dynamic property to that.
And if they are moving in and moving out
of the nuclear pore complex, clearly when you
have stress granules they're sequestering them
and therefore they can't become incorporated back
into the pore and we see that.
And followup studies from our cell paper we actually
can look at individual nuclear pore complexes
and see that they're missing these proteins
in the setting of stress.
How do you use this information?
Aside from helping dissect a mechanism of disease
is there a way to then mitigate this injury?
So one would be what if you could minimize
the formation of stress granules?
Would you, aside from other cellular processes
that stress granules are associated with, could
this prevent the injury to nuclear pores?
And the absolute answer is yes.
And we've done that both in the paper and followup studies.
That you can minimize the injury to nuclear pore complexes
by preventing the stress granule formation.
And one of those proteins by a colleague Aaron Gitler.
Known as Ataxin-2, we already know that if you remove that
and therefore mitigate some of the stress granules.
Animal models of disease, of ALS in fact,
are really slowed down.
And there are already design efforts under way
to make Antisense Oligonucleotides that mitigate,
that knock down Ataxin-2 as a way
of actually slowing the disease.
Those are trials actually thought of for patients.