The Scientist November 2018

THE PAPER

B. Eftekharzadeh et al., “ Ta u protein disrupts

nucleocytoplasmic transport in Alzheimer’s

disease,” Neuron, 99:925–40.e7, 2018.

Dotted along the edges of neuronal cells’

nuclei are protein complexes that act like bor-

der agents, carefully monitoring the RNAs

and proteins that move into and out of the

command center of the cell. Disruptions at

the border—such as an improper flux of cer-

tain proteins—can cause problems for the cell

and may underlie Alzheimer’s disease (AD)

and other neurological conditions.

Researchers have previously linked

defects in the gatekeeping protein struc-

tures—called nuclear pore complexes—

with aging, amyotrophic lateral sclerosis,

and other neurological diseases. But a new

study “demonstrates that nuclear pore

impairment seen in AD is likely a primary

target of the disease, rather than a non-

specific defect,” Hong Joo Kim, a cell and

molecular biologist at St. Jude Children’s

Research Hospital who was not involved

in the work, tells The Scientist.

Past studies have shown that nuclear

pore impairment is related to rogue tau

proteins moving from the microtubules

in the axons of neurons to the cytoplasm.

Clumping of the tau proteins has long been

associated with AD. Bradley Hyman, a neu-

rologist at Massachusetts General Hospi-

tal and Harvard Medical School, and col-

leagues wanted to understand exactly how

tau is involved in neuronal cell damage. By

staining and imaging tau and other pro-

teins in the brains of humans with and

without the disease and in wildtype mice

and transgenic mice expressing mutant

human tau, the team found that tau inter-

acts directly with Nup98, a building block

of nuclear pore complexes. In diseased

brains, some Nup98 appears to be misdi-

rected to the cytoplasm. In addition, exper-

iments in cultured cells in which Nup98

was placed in the cell cytoplasm showed it

helped to enhance tau aggregation there.

“The neatest part of the research is that

we may have found a mechanism of toxicity

for tau,” Hyman says. Ta u appears to draw

Nup98 out of the nuclear pore complex,

disrupting its operations, and then Nup98

helps tau aggregate, leading to cell death.

Ta u aggregates did seem to alter

nucleocytoplasmic transport, Roy Parker,

a biochemist at the University of Colo-

rado Boulder who coauthored a perspec-

tive accompanying the new paper, writes

in an email to The Scientist. However, “I

was not convinced that the interaction

with Nup98 was the fundamental mech-

anism behind this effect,” he says. Many

protein aggregates disturb movement

between the nucleus and cytoplasm, he

explains, but not all of the mechanisms

are well understood, and others may be at

work in Alzheimer’s disease.

“A n important question that remains

to be answered is whether the interac-

tion of disease-associated proteins with

Nup98 is specifically important to initiate

the pathogenesis,” Kim says. It will also be

interesting, she adds, to find out whether

other disease-related proteins directly

interact with components of the nuclear

pore complex. Still, the new study, she

notes, does suggest drugs reducing protein

aggregation or preventing tau aggregates

from interacting with nucleoporins could

provide some benefit in AD and other neu-

rodegenerative diseases.

—Ashley Yeager © TAMI TOLPA

52 THE SCIENTIST | the-scientist.com

The Literature

NEUROSCIENCE

Disrupting the Flow

EDITOR’S CHOICE PAPERS

TRAFFIC: In healthy neurons (left), tau protein is confined to microtubules. But in Alzheimer’s, tau aggregates

disrupt the flow of proteins and RNA into and out of the nucleus of neuronal cells and also draw the protein into

the cytoplasm (right). Nup98’s presence in the cytoplasm leads to continued aggregation of tau into the neurofi-

brillary tangles that serve as a signature of Alzheimer’s disease.

Nuclear pore

complex

Nup98

Nucleus Ta u

Ta u

Nup98

Tau

Healthy neuron Diseased neuron

Microtubules

Proteins

RNA