HHMI investigator David Chan, at the California Institute of Technology, studies the links between human diseases and mitochondrial membranes.

At times, the cell requires a more monumental shift in membranes than protein transport by vesicles. Sometimes an entire organelle needs to move or change shape or size. Unlike most houses, designed with immovable walls, cells can rearrange their insides as needed.

Tom Rapoport, an HHMI investigator at Harvard Medical School, wants to know how cells achieve this fluidity. His team has probed the biochemistry of various membrane channels; now they're dabbling in questions of membrane architecture—and are seeing connections to disease.

The lab group specifically studies how the cell generates the elaborate network of interconnected sheets and tubules that make up the ER. The ER is sheet-like nearest the nucleus of the cell and consists of more tubules near the periphery of the cell. In different stages of the cell's life cycle, the balance of sheets and tubules changes. Scientists are only beginning to understand how it happens.

In 2006, Rapoport identified two families of proteins—reticulons and DP1s—that shape the lipids of the ER into tubules. In a test tube, lipids mixed with these proteins spontaneously arrange themselves into tubules. More recently, in an August 2009 paper in the journal Cell, Rapoport and his collaborators pinpointed a protein—atlastin—that causes fusion between tubules. This mechanism could be responsible for generating a tubular network and may well be what the cell uses to shift its balance of tubules and sheets, says Rapoport.

Scientists have linked a mutation in atlastin with a neurological disease: hereditary spastic paraplegia, characterized by progressive weakness and stiffness of the legs. The disease is caused by shortening of axons, the long slender fingers that project outward from neurons to relay messages from the body's extremities to the brain.

Rapoport's study linking atlastin to tubule fusion—and more specifically, ER fusion—offers an explanation for spastic paraplegia. Without ER fusion, it's likely that the ER network in long neuron cells can't extend far. “If the ER network is not extending all the way,” says Rapoport, “that's causing problems at the ends of the axons.”

Interestingly, an analogous problem in plants has been linked to defects in ER morphology. Plants with a mutation in a protein that functions like atlastins have short wavy root hairs in places where the roots should be long. In both cases, the ER's inability to mold its membranes has tremendous consequences.

For other diseases, though, the culprit is the equilibrium between the fission and fusion of a different organelle: the mitochondrion.

Jill Connelly/AP, ©HHMI

	PAGE 1 2 3 4 5	Go Back | Continue