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24 April 2014 11:45 am ,
Vol. 344 ,
The National Institutes of Health is revising its "two strikes" rule, which allowed researchers only one chance to...
By stabilizing the components of retromers, molecular complexes that act like recycling bins in cells, a recently...
Fossil fuels power modern society by generating heat, but much of that heat is wasted. Semiconductor devices called...
Researchers are gaining insights into what made Supertyphoon Haiyan so powerful and devastating through post-storm...
Millions around the world got a first-hand look at what it was like to be in Tacloban while it was pummeled by...
Major climate data sets have underestimated the rate of global warming in the last 15 years owing largely to poor data...
The tsetse fly is best known as the vector for the trypanosome parasites that cause sleeping sickness and a disease in...
- 24 April 2014 11:45 am , Vol. 344 , #6182
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More Blame for Killer Clumps
19 May 2003 (All day)
The inherited form of Lou Gehrig's disease--familial amyotrophic lateral sclerosis (FALS)--causes a decay of the motor neurons in the spinal cord and brain, a devastating loss of bodily control, and death within 2 to 5 years. A study now shows that the molecular cause of FALS is similar to that of other neurological illnesses such as Huntington's and Alzheimer's diseases, offering new hope in the search for a treatment.
FALS patients carry mutations in a gene called superoxide dismutase (SOD1), but it's a puzzle how these mutations lead to the disease. Normally, the SOD1 protein binds zinc and copper atoms and uses them to break down superoxide, a destructive byproduct of cellular respiration. So it would make sense if the mutations cripple the SOD1 proteins, allowing superoxide to build to toxic levels. But this idea was ruled out when researchers found that mice lacking the SOD1 gene remain healthy. Only a mutated copy causes paralysis, indicating that mutated SOD1 is itself the toxic agent behind FALS.
Because a protein's abilities are determined by its shape, a team led by John Hart at the University of Texas Health Science Center in San Antonio used x-ray crystallography to see how mutation alters SOD1's protein structure. Reporting in the 18 May issue of Nature Structural Biology, Hart and his colleagues reveal that mutation can cause SOD1 proteins to lose their metals, exposing patches that have just the right shape and charge for the proteins to lock onto each other. These new interfaces link SOD1 into ever-growing fibrils which may overwhelm the protein-degrading systems that cells use to keep themselves tidy, a pathology known from other neurodegenerative disorders. With this mechanism revealed, Hart hopes to identify drugs that would inhibit this destructive binding.
The quality of the work is "breath-taking," says Mark Gurney, vice president of drug discovery at deCODE Genetics in Reykjavík, Iceland. But before drug research can begin in earnest, Gurney says it will be important to prove that this aggregation mechanism occurs "inside motor neurons, not just in protein crystals."