Zip Code Spurs Cargo Transport In Neurons, Researchers Find

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" Zip Code " Spurs Cargo Transport In Neurons, Researchers Find

http://www.medicalnewstoday.com/medicalnews.php?newsid=55060

For the first time, researchers have identified a peptide that can

spur cargo transport in nerve cells, a discovery that could help

scientists better understand nerve cell function and test possible

therapies for neurodegenerative diseases.

Elaine Bearer, a professor at Brown Medical School, led the

research, which was conducted at the MBL (Marine Biological

Laboratory) in Woods Hole, Mass., where Bearer was a Dart Scholar

and is a Whitman investigator. Published in the Proceedings of the

National Academy of Sciences online early edition, the research

shows that a peptide, or protein bit, can hitch biological material

onto molecular motor machinery, acting as a " ZIP Code " that directs

the shipment to the synapse.

The peptide comes from amyloid precursor protein, or APP, a

principal component of plaques found in the brains of people with

Alzheimer's disease. Scientists have long known that APP can break

down and form these plaques and that mutations in this protein lead

to early onset of Alzheimer's disease. Until now, however, little

was understood about the function of APP in healthy nerve cells.

The research also sheds light on the complex intracellular transport

system inside nerve cells. This transport system is critical to

nervous system function, bringing proteins and RNA from the cell

body down a neuron's spindly axon to the synapse, the major site of

information exchange and storage in the nervous system. Without this

precious cargo, neurons can't communicate. Memories can't be made.

Learning can't take place. And neurons die.

" This neuronal transport system is incredibly important, but until

now, we didn't know what actually attaches the cargo to the motor

and gives it a 'ZIP Code' or address to ship it to. Our work shows

that the cargo-motor hitch is as simple as a short peptide, " Bearer

said. " We've identified the first of these molecular dispatchers – a

short peptide from the Alzheimer's protein APP. "

At Brown, Bearer studies molecular transport through the herpes

simplex virus (HSV), which travels inside neurons between the cell

body and synapse. At her MBL laboratory, she studies the general

mechanisms governing transport by injecting fluorescently labeled

virus into the giant axon of the squid.

Aside from being a seafood delicacy, squid have a giant axon, or

nerve cell fiber, that is 1,000 times wider than the average human

axon, making it much easier to see and work with. For more than 75

years, squid have helped MBL scientists demystify important nervous

system functions, such as how nerve cells communicate; how proteins,

organelles, and other cargoes are transported along the axon; and

how nerves conduct electricity. Since all life forms have similar

basic cellular functions, scientists can translate what they learn

from a simple system like the squid's to the more complex system in

humans.

The Bearer lab has already shown that APP is physically associated

with the herpes virus during anterograde transport, or the movement

from the cell body to the synapse. In this new work, Bearer wanted

to test whether APP was capable of mediating this movement.

In the lab, Bearer and her team substituted fluorescent beads for

virus and coated them with chemically synthesized peptides based on

the sequence of human and squid APP. The squid sequence was obtained

through a new squid genome project initiated at MBL by study co-

author ph DeGiorgis. Bearer and her team injected the beads into

squid axon then watched through a microscope. Would the beads move?

If they did, what path did they take? And where would they wind up?

After testing seven different peptides, Bearer and her team found

that only one, a short peptide from APP, which they called APP-C,

made the beads move quickly down the axon to the synapse. What's

particularly compelling about the finding, Bearer said, is that APP-

C in squid can be found in a nearly identical form in humans, worms

and fruit flies, making it likely that the peptide plays a universal

role in cargo trafficking inside neurons and other cells.

The peptide tag could be used to tag protein therapy aimed at

repairing synapses damaged by disease or by poisons such as lead.

Scientists could use the tag as a research tool to help them better

understand nerve cell transport. It might also be also be used in

diagnostic studies to determine whether and how much transport has

been affected by dementia or to trace normal or abnormal neuronal

circuits.

Bearer said the research results point to APP transport as a

possible drug target for Alzheimer's, Huntington's and other

diseases characterized by a breakdown in nerve cell transport.

" We've created a protein delivery system that we can use for all

kinds of basic bench research as well as to test biomedical

therapies, " Bearer said. " The possibilities are exciting. "