Lethal legos. SOD1 mutant proteins link together strings constantly increasing.
The inherited form of Lou Gehrig disease amyotrophic lateral sclerosis -familial (FALS) - causes disintegration of the motor neurons of the spinal cord and brain, a devastating loss of control the body, and death within 2 to 5 years. A study now shows that the molecular cause of FALS is similar to other neurological diseases such as Huntington's and Alzheimer's disease, offering new hope in the search for a cure.
Fals patients with mutations in a gene called superoxide dismutase ( SOD1 ), but it is a puzzle how these mutations lead to disease. Normally, the SOD1 protein binds zinc and copper atoms and uses them to break superoxide, a destruction of cellular respiration byproduct. So it would be logical if the mutations cripple the SOD1 protein, superoxide to build to toxic levels. But this idea was discarded when the researchers found that mice lacking the SOD1 gene remain healthy. Only one mutated copy causes paralysis, indicating that mutated SOD1 is itself toxic agent behind FALS.
Because the capacity of a protein is 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 the mutation alters the structure of the protein of SOD1. Reporting in May 18 issue of Nature Structural Biology , Hart and colleagues show that the mutation may cause SOD1 proteins to lose their metals, exposing patches that have just the right shape and charge for proteins to lock onto each other. These new SOD1 link interfaces always growing fibrils that can overwhelm systems degrading proteins that cells use to keep themselves tidy, known pathology other neurodegenerative disorders. With this revealed mechanism, Hart hopes to identify drugs that inhibit the destructive link.
The quality of work is "breathtaking," said Mark Gurney, Vice President of Drug Discovery at deCODE Genetics in Reykjavik, Iceland. But before seeking the drug can begin in earnest, Gurney said, it will be important to demonstrate that this aggregation mechanism occurs "inside motor neurons not only in protein crystals."
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