Researchers characterize novel lysosomal PQ protein linked to cystinosis

Nov 23 2012

Researchers at the Université Paris Descartes/CNRS and the Université libre de Bruxelles have made a major breakthrough in the study of cystinosis, a genetic disease that can lead to serious disorders, notably fatal kidney failure.

Cystinosis is a genetic disease characterized by an abnormal accumulation of the amino acid cystine in various organs of the patient's body (kidneys, eyes, muscles, pancreas and the brain), at different ages of his life. Cystinosis occurs when the protein cystinosin, located on the lysosomal membrane, fails to transport the cystine out of the lysosome. Defective transport of cystine can lead to a toxic concentration of this amino acid in the lysosome, causing severe impairment, notably in the kidneys.

Cystinosin is regarded as the prototype of a novel membrane protein family: "PQ" motif proteins, the subject of study by Dr. Bruno Gasnier and his team of researchers at the Université Paris Descartes/CNRS. The molecule was identified in 1998 by Dr. Corinne Antignac, Paris Descartes University, and her "Hereditary Nephropathies and Kidney Development" research unit.

Working in collaboration with Bruno André, the director of the Laboratory of Molecular Cell Physiology at the Université libre de Bruxelles (ULB), Dr. Gasnier has broken new ground in the study of cystinosis. The researchers were able to characterize a novel lysosomal PQ protein whose role is to catalyze the transport of basic amino acids (arginine, lysine and histidine) into the cytoplasm.

Their research is published in the November 19-23 edition of PNAS

Although scientists had discovered the existence of such a protein possessing a metabolic function in man two decades ago, attempts to identify it biochemically and to clone its gene had repeatedly failed, until now.

The first experiments on the yeast model, conducted by Dr. André and his research team (ULB), uncovered three PQ motif proteins that are present in the vacuolar membrane (the yeast lysosome) and are involved in the transport of basic amino acids. Bioinformatics analysis subsequently revealed that these yeast proteins have a mammalian equivalent, and collaboration with Dr. Agnès Journet from the Atomic Energy Commission, the National Institute of Health and Medical Research and the Joseph Fournier University (Grenoble), established its presence in the lysosomal membrane.

Bruno Gasnier and his team of researchers at the Université Paris Descartes/CNRS then undertook the study of this protein, termed PQLC2. Their experiments revealed that PQLC2 transports the three basic amino acids, a function crucial to cellular metabolism.

What is the link between this newly identified lysosomal protein transporter and cystinosis, the genetic disease caused by a defect in cystine transport? Patients with cystinosis are currently treated by a therapeutic molecule, cysteamine, which condenses with the cystine present in the lysosome and converts it into a compound chemically close to a basic amino acid, lysine. The new compound then becomes capable of leaving the lysosome.

The study conducted by the French and Belgian scientists shows that the novel transporter protein, PQLC2, is responsible for expelling this "life-saving" molecule from the lysosome. Their findings provide valuable insights into the mechanism of cystinosis treatment, thereby opening new perspectives for research in understanding the disease and in finding more effective ways of treating it.

This work was made possible through the support of the Cystinosis Research Foundation