Researchers at the University of Wisconsin-Madison and collaborators have discovered a powerful new protein that may shed light on age-related macular degeneration, Alzheimer's disease, Huntington's, Parkinson's, and other diseases related to nerve degeneration. All of these disorders may be linked to the malfunction of similar but yet-to-be-identified proteins in the eye and brain.

The new protein, which the scientists have named XPORT, is a molecular "chaperone" for two other important proteins that are key to sensory activities in the eye.

Rhodopsin is a protein that is responsible for absorbing light. The other protein, TRP, is a channel that plays a role in calcium influx into cells. XPORT guides these two proteins from the place where they are manufactured in the cell to the location where they do their jobs.

This intricate process of chaperoning includes synthesis, folding, assembly, quality control, transport and targeting of proteins to their appropriate locations, explains senior author Dr. Nansi Jo Colley of the UW School of Medicine and Public Health. The complex process is prone to error, and a malfunction in any of the steps can have dire consequences in tissues.

A malfunction in any of the steps can have dire consequences in tissues, said study co-author Dr. Nansi Jo Colley, a professor in the Department of Ophthalmology and Visual Sciences at the University of Wisconsin School of Medicine and Public Health.

"Accumulation of misfolded proteins often leads to severe pathology and cell death, producing blinding diseases and other neurodegenerative diseases," says Colley, a professor in the Department of Ophthalmology and Visual Sciences, the Department of Genetics and the Eye Research Institute. "Molecular chaperones are one of the first lines of defense in these fundamental processes."

The team of researchers discovered XPORT while studying fruit flies with damaged retinas. Those with malfunctions in the function of XPORT displayed retinal degeneration and defects in rhodopsin and TRP, they found.

According to the researchers, XPORT forms a complex with rhodopsin and TRP and is required to successfully transport the two proteins to a specific location on the cell surface. Colley and the team of researchers also determined that XPORT is essential for cell survival. Mutations in XPORT prevented the two proteins from moving through the trafficking pathway and this ended in retinal degeneration and blindness in the fly.

TRP channels play a vital role as biological sensors, Colley said. They regulate calcium entering cells that are involved in vision, taste, olfaction, hearing and touch. "Defective TRP channels can cause night blindness in certain people," Colley said.

XPORT was also found to interact closely with heat shock proteins, another family of molecular chaperones. "Heat shock proteins have also been implicated as agents that protect nerve cells from degeneration," Colley says, "so XPORT or XPORT-like proteins might have therapeutic potential as well."

Colley said that a protein very similar to XPORT also may be present in humans.
The study was published in the November 16 issue of Neuron.

Adapted from the University of Wisconsin School of Medicine and Public Health

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