Study Revises Dynamin's Role In Nerve Cell Function

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Study Revises Dynamin's Role In Nerve Cell Function

http://www.medicalnewstoday.com/medicalnews.php?newsid=70718

An unexpected finding on how nerve cells signal to one another could

rewrite the textbooks on neuroScience, says a collaborative team of

researchers at Weill Cornell Medical College and Yale University.

Their study, published as a high-profile research article in the

journal Science, suggests that a key cellular enzyme called dynamin

1 is not essential to all synaptic transmission, as experts had

previously assumed.

Dynamin has long been a focus of research for its role in packaging

chemical signals, called neurotransmitters, into tiny synaptic

vesicles within the cell.

The new study finds that the enzyme is not always necessary for this

process. Instead, dynamin 1 goes into action only when the synapse

enters moments of especially high activity.

" In that sense, dynamin 1 remains crucial, allowing the synapse the

freedom to function under all conditions, " explains co-senior author

Dr. , professor of biochemistry at Weill Cornell Medical

College.

The discovery is a potentially important new piece of the puzzle for

scientists investigating neurological injury and disease.

" In the long run, what we're trying to achieve here is a kind of

biochemical 'repair manual' for the brain and brain cells, " Dr.

explains. " So, in the future, if we find out that a particular

illness is caused by a flaw in dynamin 1 function or proteins that

interact with dynamin 1, we'll have answers on hand to help fix

that. "

Dynamin 1 is one of a family of enzymes involved in synaptic vesicle

endocytosis -- a reverse of the process of transmission of cellular

signaling chemicals, whereby molecular components of the vesicle are

retrieved from the synapse surface and fit back into a new vesicle

to be recycled for reuse after the vesicle has discharged its

neurotransmitter. One of the steps in this recycling is a

biochemical process called fission.

" Early work with the Drosophila fruit fly established dynamin 1's

role in this vesicle recycling process, " Dr.

explains. " Essentially, the enzyme undergoes a chemical change

whereby it physically squeezes off a piece of the old vesicular

membrane -- creating a brand new vesicle poised to take on a new

load of neurotransmitter. "

Based on this work in fruit flies, neuroscientists had assumed that

dynamin 1 was necessary for the growth and function of all synaptic

transmission.

But Dr. , along with co-senior author Dr. Pietro De Camilli, a

Medical Institute investigator and professor of cell

biology at Yale, decided to test that notion.

Dr. De Camilli's laboratory in New Haven had worked hard to develop

a unique, genetically engineered mouse without dynamin 1. If the

enzyme was essential to all synaptic activity, these mice would die

very soon after birth.

But the pups were born, and initially appeared healthy. " That was

the really big surprise here, " Dr. says. " Pups lacking dynamin

1 moved and suckled just like normal pups at birth. "

Lab study revealed that synaptic activity in these mice was

functioning at a low level -- enough to keep the mice alive over the

short term -- without dynamin 1.

" The enzyme's function appears to be much more subtle than we had

imagined, " Dr. says. " It may not be necessary under conditions

of low synaptic activity. In those cases, we suspect that other

related enzymes, such as dynamin 2 and 3, may shoulder the load and

carry out some residual function. "

" But as soon as cells require higher levels of synaptic activity,

dynamin 1 becomes absolutely necessary, " he says.

Normal growth and function demand that neurons work at high

capacity, so young mice without dynamin 1 eventually did die off,

usually within a week or two of birth.

" These findings really change our outlook on dynamin 1, and on

synaptic vesicle endocytosis in general, " Dr. says. " It's an

exciting new discovery, one that we didn't expect. But all good

Science is built on surprises. "

This work was funded by the G. Harold and Leila Y. Mathers

Charitable Foundation, the U.S. National Institutes of Health, AIRC

(Associazione Italiana per la Ricerca sul Cancro), AICR (American

Institute for Cancer Research), Telethon (an Italian foundation),

FIRB (Fondo per gli investimenti per la ricerca di base) and

COFIN/PRIN, the Canadian Institutes of Health Research, the Human

Frontiers Science Program, and the Federazione Italiana per la

Ricerca sul Cancro.

Co-researchers include lead author Dr. M. Ferguson, Mitsuko

Hiyashi, Chiara Collesi, Dr. Silvia Giovedi, Dr. Raimondi,

Dr. Liang-Wei Gong, Dr. Flavell and Summer Paradise -- all

of the HHMI and Yale University; Dr. Markus Wolfel and Dr. Gero

Miesenbock, of Yale University; Dr. Gabor Brasnjo, of Weill Cornell

Medical College; and Dr. Pablo Ariel, of Weill Cornell Medical

College and The Rockefeller University.