Sci. Aging Knowl. Environ., 6 July 2005
Out-of-shape proteins speed death in neuron-destroying disease
A squirming 5-year-old is annoying, but proteins that can't settle down might be lethal, according to new work. The study suggests that unstable versions of an oxidation-battling enzyme spark the fatal nerve disorder amyotrophic lateral sclerosis (ALS). The work supports preliminary studies that used molecular guardians to keep the protein in line.
ALS ruins the motor neurons that control movement, breathing, and swallowing. As in neurodegenerative illnesses such as Alzheimer's disease, neurons in ALS teem with clumps of misfolded proteins. Whether these knots destroy neurons remains uncertain, and so does the cause of most ALS cases. However, researchers know that some inherited varieties of the disease stem from glitches in the gene for superoxide dismutase 1 (SOD1), an enzyme that quashes antioxidants emitted by metabolism (see Sampayo and Lithgow Perspective). In patients with these types of ALS, clots of SOD1 build up in neurons. Although researchers suspect that incorrectly folded SOD1 prompts the disease, they haven't corralled confirming evidence. Biochemist Mikael Oliveberg of Umeå University in Sweden and colleagues wanted to test how different SOD1 defects alter the protein's folding and whether they influence how long patients survive.
The researchers gauged the folding capability of 15 flawed forms of human SOD1 in the test tube. A working SOD1 molecule sports a pair of identical strands, and previous studies suggested that they fold in two stages. First, each strand assumes a particular shape. Then the chains interlock and accommodate each other. The team found that mutations messed up this process in three ways. Some mutations interfered with folding of individual strands, destabilizing them. Others hindered the two molecules from hooking up. A third group hampered both steps. Using data on more than 200 ALS patients, the researchers then determined the effect of each of the 15 mutations on survival. Some people had lived only a year after symptoms first appeared, while others lasted for more than 17 years. The more unstable the patient's version of SOD1, the shorter his or her survival time after diagnosis, the analysis showed. Overall, the findings support the notion that off-kilter SOD1 spurs the disease, says Oliveberg. Earlier this year, other scientists described molecules that latch onto SOD1 and prevent it from misfolding in a test tube, and the current work suggests that such molecules could be a good treatment. Furthermore, because SOD1 is easier to study than the cumbersome proteins that accumulate in Alzheimer's and Parkinson's diseases, it might help researchers understand how changes in shape spur nervous system degeneration, he adds.
The paper achieves a first by connecting patient survival with protein instability, says structural biologist Nikolay Dokholyan of the University of North Carolina, Chapel Hill. He lauds the authors for rounding up survival and mutation data on so many patients with these rare forms of ALS. However, he notes, researchers need information from even more patients to ensure that the link holds. If so, a little molecular discipline might help SOD1 to sit quietly and calm ALS.
July 6, 2005
Science of Aging Knowledge Environment. ISSN 1539-6150