Kinesin and dynein motors travel on microtubule tracks in the
nerve of a fruit fly larva. This video shows the motors' normal
behavior; when the level of presenilin was reduced in a study, the
motors increased their velocity.
BUFFALO, N.Y. — Imagine if you could open up your brain
and look inside.
What you would see is a network of nerve cells called neurons,
each with its own internal highway system for transporting
essential materials between different parts of the cell.
When this biological machinery is operating smoothly, tiny motor
proteins ferry precious cargo up and down each neuron along
thread-like roadways called microtubule tracks. Brain cells are
able to receive information, make internal repairs and send
instructions to the body, telling the fingers to flex or the toes
But when the neuron gets blocked, this delicate harmony
deteriorates. One result: diseases like Alzheimer’s.
Understanding such blockages and how traffic should flow
normally in healthy brain cells could offer hope to people with
Toward that end, a research team led by University at Buffalo
biologist Shermali Gunawardena, PhD, has shown that the protein
presenilin plays an important role in controlling neuronal traffic
on microtubule highways, a novel function that previously was
The research results were published online on May 24 in the
journal Human Molecular Genetics (http://bit.ly/ZqxSJ5).
Gunawardena’s co-authors are Ge Yang of Carnegie Mellon
University and Lawrence S. B. Goldstein of the Howard Hughes
Medical Institute and the University of California, San Diego.
Inside the nerves of fruit fly larvae, presenilin helped to
control the speed at which molecular motors called kinesins and
dyneins moved along neurons. When the scientists halved the amount
of presenilin present in the highway system, the motors moved
faster; they paused fewer times and their pauses were shorter.
Given this data, Gunawardena thinks that tweaking presenilin
levels may be one way to free up traffic and prevent dangerous
neuronal blockages in patients with Alzheimer’s disease.
“Our major discovery is that presenilin has a novel role,
which is to control the movement of motor proteins along neuronal
highways,” said Gunawardena, an assistant professor of
biological sciences. “If this regulation/control is lost,
then things can go wrong. This is the first time a protein that
functions as a controller of motors has been reported.
“In Alzheimer’s disease, transport defects occur
well before symptoms, such as cell death and amyloid plaques, are
seen in post-mortem brains,” she added. “As a result,
developing therapeutics targeted to defects in neuronal transport
would be a useful way to attack the problem early.”
The findings are particularly intriguing because scientists have
known for several years that presenilin is involved in
Presenilin rides along neuronal highways in tiny organic bubbles
called vesicles that sit atop the kinesin and dynein motors, and
also contain a second protein called the amyloid precursor protein
(APP). Presenilin participates in cutting APP into pieces called
amyloid beta, which build up to form amyloid plaques in patients
with Alzheimer's disease.
Such buildups can lead to cell death by preventing the transport
of essential materials—like proteins needed for cell
The findings of the new study mean that presenilin may
contribute to Alzheimer’s disease in at least two ways: not
just by cleaving APP, but also by regulating the speed of the
molecular motors that carry APP along neuronal highways.
“More than 150 mutations in presenilin have been
identified in Alzheimer’s disease,” Gunawardena said.
“Thus, understanding its function is important to
understanding what goes wrong in Alzheimer’s
To track the movement of the kinesins and dyneins, the team
tagged their cargo with a yellow fluorescent protein. This enabled
the scientists to view the molecular motors chugging along inside
the neuron under a microscope in a living animal. A special
computer program then analyzed the motors’ paths, revealing
more details about the nature of their movement and how often they