Protein chaperone bulwark against nerve degeneration (3/19/2008)

A protein called NMNAT (NAD synthase nicotinamide mononucleotide adenylyltransferase) protects nerve cells from degeneration by acting as a "chaperone," a molecule that helps other proteins fold into an active state, said researchers from Baylor College of Medicine in Houston in a report that appears in the current issue of the journal Nature.

Dr. Hugo Bellen and others in his laboratory had already determined that NMNAT protected nerve cells from degenerating in a previous work. Now they have found that NMNAT accomplishes this task by acting as a chaperone.

Bellen is a professor of molecular and human genetics, molecular and cellular biology and neuroscience. He is director of the BCM Program in Development Biology and a Howard Hughes Medical Institute investigator.

"Chaperones ensure that when other proteins unfold and become inactive they can be refolded and be active again," he said. Proteins must fold into specific conformations that allow them to work with the other cellular machinery - much as keys fit into locks.

Neurodegenerative diseases often begin when proteins aggregate abnormally in the cell. NMNAT, in its chaperone role, works to prevent that, said Bellen.

"When a protein opens up, the hydrophobic (water aversive) residues become exposed," he said. "Not only is the protein nonfunctional, but it begins to aggregate" as the water aversive parts of one protein gravitate toward similar parts of another.

The chaperone actually covers up these hydrophobic residues, preventing protein aggregation. Then, when the chaperone moves off, the protein has a chance to fold again before being attracted to the other proteins and becoming part of an aggregate. Degrading and getting rid of these aggregates can take up much of a cell's energy. If the aggregates remain, they can interfere with the cell's normal activities.

In fruit flies bred to lack NMNAT, degeneration occurs when the nerves are active. For example, the photoreceptors in the eyes of flies without NMNAT die quickly when they are exposed to light. If the flies live in the dark, the photoreceptors live longer. They are less active and they do not degenerate.

Bellen and his colleagues decided to find out what happened when ataxin-1, a protein associated with a human neurodegenerative disorder called spinocerebellar ataxia type 1, occurs at high levels in the neurons of the flies. Ataxin was shown previously to cause nerve cells in the retina to die. However, if they also caused cells to make higher than normal levels of NMNAT, the retinas regained their normal configuration.

"Every time we overexpress this protein (NMNAT), it protects against endogenous (existing) toxicity or induced toxicity," said Bellen.

When ataxin is overexpressed in cells, they form large aggregates. However, when NMAT is also overexpressed, the large aggregates become smaller.

"NMNAT helps to reduce the size of the aggregates and make the protein more soluble," said Bellen. NMNAT exhibits all the attributes of a chaperone, he said. It goes to the aggregated proteins and tries to help them fold, reducing the size of the aggregate.

NMNAT is already known to act as an enzyme, and some researchers had considered that perhaps its enzymatic activity somehow prevented neurodegeneration. However, even when the portion of NMNAT that governs the enzymatic activity is lopped off, it still protects the nerve cells, buttressing the argument that it is acting as a chaperone in this instance. In other words, the protein is "moonlighting": it's not just an enzyme producing NAD, it is also a chaperone.

Others who took part in this research include Fan Zhang, P. Robin Hiesinger, Yu Cao and Claire M. Haueter of BCM, and first author R. Grace Zhai, formerly at BCM and now Assistant Professor at the Miller School of Medicine at the University of Miami.

Support for this research came from the Howard Hughes Medical Institute, the PhRMA Foundation, the Florida Department of Health and the Esther King Biomedical Research Program. Confocal imaging was supported by the BCM Mental Retardation and Developmental Disabilities Research Center and imaging assistance was given by the Analytical Imaging Core Facility at the University of Miami.

Note: This story has been adapted from a news release issued by the Baylor College of Medicine

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