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sciencemag.org SCIENCEtein called RanGAP, stood out. Fifteen days
after the flies emerged from their pupal cas-
ings, their eyes remained a pure burnt sienna.
RanGAP “was by far the most potent suppres-
sor of neurodegeneration,” Lloyd says. What
was known about its function was tantaliz-
ing: It serves as a courier, helping shuttle
other proteins across the membrane that
divides the cell nucleus from the cytoplasm.
The team’s result would upend neuro-
scientists’ understanding of ALS and brain
disease in general, and others were on the
same trail. In 2015, two more research teams
reported that defects in the cell’s nuclear
transport system were hallmark features not
only of ALS, but also of frontotemporal de-
mentia (FTD), another progressive brain dis-
ease caused by C9orf72 mutations. Scientists
would soon link dysfunctional trafficking
across the nuclear divide to other neurode-
generative diseases—Alzheimer’s, Hunting-
ton, spinocerebellar ataxia—and even to
normal aging. In all those ailments, the re-
sulting abnormal pileups of proteins some-
how become rogue neuronal killers.
“I often get queasy when someone makes a
discovery and tries to explain the rest of the
world with it,” says Rothstein, a neurologist
who directs the Johns Hopkins Brain Sci-
ence Institute. But here, he says, it seems
to be true.
The findings are not merely academic.
They are inspiring therapeutic efforts to
address the cause of general age-related
neurodegeneration—a goal that has largely
eluded drug developers. If the gradual loss
of nucleocytoplasmic transport is a con-
served feature of the aging brain, says Sami
Barmada, a neurologist at the University of
Michigan in Ann Arbor, preventing it “might
be a really broad and effective therapy.”
Several biotech companies have jumped
on that idea, exploring it in animal models
and planning the first human trials this year.
Chief among them: Biogen in Cambridge,
Massachusetts, which in 2018 bought the
rights to develop a drug compound called
KPT-350 that directly targets the nuclear
transport pathway. The research under-
pinning that drug’s action is brand new. But,
“The biology is there,” says Chris Henderson,
head of neuromuscular and movement disor-
ders research at Biogen. “Here’s a drug with
a body of rationale,” he adds, “and we’re opti-
mistic about getting this into trials.”
THE LIPID MEMBRANE that divides the DNA-
packed nucleus from the rest of the cell is
like an international border busy with two-
way industrial traffic. DNA-binding pro-
teins and other molecules are constantly
flowing into the nucleus to help turn genes
on and off, for example. The messenger
RNAs produced by those genes stream the
other way, into the cytoplasm to protein-
assembly platforms. The cell must regulate
that traffic through entry points known as
nuclear pores. Choke off those portals and
it stands to reason cells will suffer.
The first hints that disrupted nuclear
transport might underpin ALS came in
2010, when researchers at King’s College
London, working with human nerve cancer
cells, experimentally blocked the expression
of proteins involved in the import business.
The result was something also seen in cells
from ALS patients: clumps of a protein
called TDP-43 building up in the cytoplasm.
Few ALS researchers paid much atten-
tion to that early report. What might be
gumming up the gears of the transportmachinery in ALS patients wasn’t clear,
and the researchers couldn’t say whether
the buildup of TDP-43—a protein that nor-
mally binds both DNA and RNA inside the
nucleus to regulate multiple steps in gene
expression—was actually killing neurons or
was just a consequence of a different toxic
process. It would take another 5 years—and
Lloyd’s and Rothstein’s study of the flies
with telltale eyes—for ALS scientists to take
nuclear transport more seriously.
The Hopkins team’s result electrified col-
leagues in part because it had identified a
transport protein, RanGAP, as key to neuro-
degeneration. The team showed in both the
fly model of ALS and in cells from human
patients that the lengthy RNA readouts pro-duced by the mutant C9orf72 gene seemed
to stick to RanGAP near the nuclear pore
and put the protein out of commission.
The loss of functioning RanGAP spurred a
backup of the nuclear import system, result-
ing in the cytoplasmic buildup of proteins
such as TDP-43—cluttering a cell like bags
of rotting trash during a garbage strike.
Just as galvanizing was the team’s finding
that a potential drug could preserve neuro-
nal health, at least in the flies. “All of a sud-
den it threw a potential treatment approach
into the ring,” says Dorothee Dormann, a
biochemist from Ludwig Maximilian Uni-
versity in Munich, Germany.
The team had no drug that could boost lev-
els of RanGAP in the cytoplasm and restoreenough inflow to rescue the eye neurons.
But Lloyd reasoned that blocking outflow of
TDP-43 and other nuclear proteins may have
the same beneficial effect. An experimental
compound called KPT-276 was known to
selectively inhibit a key nuclear export pro-
tein called exportin 1 (XPO1). The approach
was a hack of sorts, marrying two wrongs—
defective inflow and outflow—to make a right,
but it worked. When Lloyd gave KPT-
to his ALS flies, their eyes remained pristine.KPT IS THE experimental compound code
used by Karyopharm Therapeutics, a small
drug company in Newton, Massachusetts.
Karyopharm formed in 2008 to develop
XPO1 inhibitors for treating cancer, the ideaRanGAP ImportinExportinRanC9orf72 RNAK P T- 3 5 0TDP-Nuclear
poreStress granuleCytoplasmGRAPHIC: V. ALTOUNIAN/SCIENCENormal
Importin proteins bring TDP-
and other cargo from the cytoplasm
through the nuclear pore, whereas
exportins take molecules out.ALS
In some ALS cases, abnormal RNA
made by a mutant C9orf72 gene
prevents RanGAP from mediating
nuclear import, leading to protein
buildup in stress granules.ALS + drug
A possible drug, KPT-350, impairs
the specific exportin XPO1 and may
normalize nuclear traffic of proteins
or bust up stress granules.222 18 JANUARY 2019 • VOL 363 ISSUE 6424
Fixing traffic jams
The flow of molecules through pores
in the nucleus is key to the health
of cells, particularly neurons. Traffic
problems may contribute to
amyotrophic lateral sclerosis (ALS)
and other brain diseases.Published by AAASon January 20, 2019^http://science.sciencemag.org/Downloaded from