In that sense, dynamin 1 remains crucial, allowing the synapse the freedom to function under all conditions," explains co-senior author Dr. Timothy Ryan, 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. Ryan 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. Ryan 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. Ryan, along with co-senior author Dr. Pietro De Camilli, a Howard Hughes 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. Ryan 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. Ryan 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. Ryan 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. Shawn M. Ferguson, Mitsuko Hiyashi, Chiara Collesi, Dr. Silvia Giovedi, Dr. Andrea Raimondi, Dr. Liang-Wei Gong, Dr. Richard 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.
Weill Cornell Medical College
Weill Cornell Medical College — located in New York City — is committed to excellence in research, teaching, patient care and the advancement of the art and science of medicine. Weill Cornell, which is a principal academic affiliate of NewYork-Presbyterian Hospital, offers an innovative curriculum that integrates the teaching of basic and clinical sciences, problem-based learning, office-based preceptorships, and primary care and doctoring courses. Physicians and scientists of Weill Cornell Medical College are engaged in cutting-edge research in such areas as stem cells, genetics and gene therapy, geriatrics, neuroscience, structural biology, cardiovascular medicine, AIDS, obesity, cancer and psychiatry — and continue to delve ever deeper into the molecular basis of disease in an effort to unlock the mysteries behind the human body and the malfunctions that result in serious medical disorders. Weill Cornell Medical College is the birthplace of many medical advances — from the development of the Pap test for cervical cancer to the synthesis of penicillin, the first successful embryo-biopsy pregnancy and birth in the U.S., and most recently, the world's first clinical trial for gene therapy for Parkinson's disease. Weill Cornell's Physician Organization includes 650 clinical faculty, who provide the highest quality of care to their patients. For more information, visit www.med.cornell.edu.
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