SCIENCE sciencemag.org

T

he compound eyes of the common

fruit fly are normally brick red. But

in neurologist Tom Lloyd’s lab at

Johns Hopkins University School of

Medicine in Baltimore, Maryland,

many of the fly eyes are pocked

with white and black specks, a

sign that neurons in each of their

800 -odd eye units are shriveling

away and dying.

Those flies have the genetic equivalent of

amyotrophic lateral sclerosis (ALS), the de-

bilitating neurodegenerative disorder also

known as Lou Gehrig’s disease, and their

eyes offer a window into the soul of the

disease process. By measuring the extent

of damage to each insect’s eyes, researchers

can quickly gauge whether a drug, genetic

modification, or some other therapeutic in-

tervention helps stop neuronal loss.

Those eyes have also offered an answer to

the central mystery of ALS: just what kills

neurons—and, ultimately, the patient.

The flies carry a mutation found in about

40% of ALS patients who have a family his-

tory of the disease, and in about 1 0% of spo-

radic cases. The mutation, in a gene called

C9orf7 2 , consists of hundreds or thousands

of extra copies of a short DNA sequence, just

six bases long. They lead to unusually large

strands of RNA that glom onto hundreds of

proteins in the cell nucleus, putting them

out of action. Some of those RNA-ensnared

proteins, Lloyd and his Hopkins colleague

Jeffrey Rothstein hypothesized, might hold

the key to ALS.

Over many months, the researchers sys-

tematically studied the role of each protein

by developing fly strains carrying both the

ALS mutation and an incapacitated or hyper-

active version of each protein’s gene. One set

of flies, bred to have elevated levels of a pro-

Disrupted flow into

and out of the nucleus

may kill neurons

By Elie Dolgin

THE BRAIN’S

TR AFFIC

PROBLEMS

The normal compound fly eye (top)

is marred by cell death in a strain

(bottom) with a mutation causing

amyotrophic lateral sclerosis.

PHO

TO

S: K

IRS

TIN M

AU

LD

ING

1 8 JANUARY 2 019 • VOL 363 ISSUE 6424 221

Published by AAAS

on January 20, 2019^

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