Yeast discovery provides new insights into familial dysautonomia

Apr 6 2005

A discovery in yeast that has important implications for finding a cure for a devastating disease of nerve cell failures -- called familial dysautonomia (FD) -- has been made by Cornell University researchers.

They have found a gene that is a major player in determining the structural and functional asymmetry of cells -- known in modern biological parlance as cell polarity. The gene, called Elp1, is critical in regulating cell polarity, such as directing growth to the tip of a cell so that a "daughter" cell can "bud" off to divide, says Ruth Collins, assistant professor of molecular medicine in the College of Veterinary Medicine at Cornell.

"This discovery is exciting because it not only gives researchers new insight into basic mechanisms of cell growth and differentiation, but also provides critical insight into the pathogenesis of FD, which may arise in large part from a lack of fully developed neurons [nerve cells]," Collins says.

Her discovery is described in a paper in the March 18 issue of Molecular Cell (Vol. 17, No. 6). The paper is available online at http://www.molecule.org/ .

FD, which is manifested soon after birth and usually results in a life span of less than 30 years, is known to be caused by a genetic defect in a protein that is the human counterpart to the Elp1 gene in yeast.

"Not only is polarity important for normal cell function, but loss of polarity is associated with disease states, such as cancer, where reversal of the molecular pathway that creates cell polarity is one of the early steps in the progression to uncontrolled proliferation," Collins says.

The goal of Collins and two of her graduate students was to study how yeast establishes cell polarity by directing new growth to an area of the cell membrane where a "bud" can begin to grow into a daughter cell. The researchers looked at cells that were defective in cell growth and found several indications that suggested that the protein the Elp1 gene codes for -- called Elp1p -- plays an important role in directing cell polarity.

Previous research results have identified Elp1p as playing a different role -- that of gene expression, an activity that occurs in the nucleus of a cell, not out near the periphery of the cell where cell growth activity occurs.

To test their new hypothesis, the researchers devised an experiment that allowed proteins to enter the nucleus but then trapped them there to see if Elp1p had important roles both inside the nucleus for transcription as well as near the cell periphery for cell polarity and growth. They found that the protein, in fact, did not try to enter the nucleus but clearly stayed in the cytoplasm, the region of the cell outside the nucleus.

"Because proteins can't carry out jobs unless they are present in the correct place at the right time, this experiment showed that there is an essential role for this protein in the cytoplasm," Collins explains. "Future work on this protein can focus on its newly described essential role in regulating cell polarity."

The discovery is important for FD because neurons direct new growth to a tip of the cell. "Without directional growth, neurons can't reach their intended targets, and if they can't reach their targets, they can't make synapses [connections between neurons]," says Collins.

Collins suspects that the neurological defects in FD patients may be due to the defective protein interfering with directional growth, thus preventing the neurons from developing correctly. Elp1p may also be necessary for the maintenance and stability of neurons, Collins says.

"Better understanding the exact cellular function of Elp1p is critical to the ultimate prize of a cure for this devastating disease," says Collins, noting that the new findings not only yield new insights into the fundamentals of cellular behavior, but also takes researchers a big step closer to that ultimate goal for FD patients.

FD is a genetic disease most commonly seen in people of Ashkenazi Jewish descent. Manifestations of FD include inappropriate perception of heat, pain and taste, excessive sweating, difficulty swallowing, vomiting, speech and motor incoordination, dramatic swings in blood pressure, poor growth and scoliosis.

The other authors on the paper are Pete Rahl and Catherine Z. Chen, both Cornell graduate students. The research was supported, in part, by a National Science Foundation grant and a New Investigator Grant from the American Heart Association.