When cells can’t take out the trash
July 19, 2012 § Leave a comment
If your garbage disposal at home conks out and you keep putting foodstuffs down the drain, your trash accumulates and causes a stinking mess. A similar problem occurs in cells when their garbage disposals, called lysosomes, fail. In a paper just out in Science, researchers have pinpointed a particular protein in lysosomes that keeps the organelle functioning normally. When the protein and others like it malfunction, lysosomal storage diseases may result.
There are more than 50 disorders involving lysosomes, and they are collectively known as lysosomal storage diseases. They usually involve the inability to break down or throw out waste through lysosomal membrane transporters.
But the problem is that “there is really not much known about the molecular mechanisms of lysosomal disorders,” although many disease-causing genes have been identified, says Xiaochen Wang at the National Institute of Biological Sciences in Beijing, China. A reason, she says, may be because there aren’t good systems for studying lysosomes.
Wang and colleagues have now shown that the nematode Caenorhabditis elegans works well as a model to study lysosomes in normal or pathological conditions, such cystinosis. Cystinosis is a rare, genetic metabolic illness that causes cystine, a dimeric amino acid, to accumulate in various organs. Without intervention, children with the disorder develop kidney failure by the age of 9.
The investigators had previously isolated a mutant worm from a genetic screen for novel regulators of cell death. This worm, which suffered from embryonic growth retardation, had a gene called laat-1 disrupted.
Wang and colleagues demonstrated that laat-1 encodes the lysosomal transporter for the amino acids lysine and arginine, “which is important for maintaining lysosomal morphology, function and amino acid homeostasis required for normal embryonic development,” explains Wang. When laat-1 is missing, lysine and arginine accumulate in bulging, dysfunctional lysosomes.
Wang says she and her colleagues will now explore if PQLC2, the human counterpart of LAAT-1, is the long-sought lysosomal transporter that mediates the effect of cysteamine, currently the most effective therapeutic agent for cystinosis. Cysteamine cuts the disulfide bond in cystine, which is the result of an oxidative reaction between two cysteines, and lets the degradation products escape the metabolic defect. The investigators will check to see if LAAT-1/PQLC2 is the transporter that carries away the degradation products.
This work shows how useful C. elegans is as a model, says Wang, because “the genetic analyses in combination with cell biological and biochemical approaches helped us to identify and reveal the function of laat-1.”
Besides focusing on PQLC2 to see if its loss has any pathological consequences in mammals, Wang says, she and her colleagues will design new genetic screens in C. elegans to search for more genes that regulate lysosome function during development or under certain pathological conditions.