The effect of gene mutations on the development of the inherited or familial form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease
In a groundbreaking study recently published in Nature Structural Biology, scientists have uncovered the effect of gene mutations on the development of the inherited or familial form of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.
Subtle but deadly differences in the shape of some, but not all, superoxide dismutase proteins lead to the formation of abnormal aggregates which, it is believed, in some way kill off the motor neurons, leaving an affected individual paralysed.
The new evidence should now make possible the future development of compounds which will cling to the mutant proteins to prevent the clumping effect.
The research team at Daresbury Laboratory led by Professor Samar Hasnain collaborated with teams at Universities of Texas, California, and Massachusetts.
High resolution pictures of the mutant proteins were obtained via three-dimensional x-ray crystallography, using the powerful X-ray synchrotron radiation facilities at Daresbury and New York. "This major breakthrough in discovering the molecular basis of this motor neuron disease has been made possible by the establishment of an international consortium, bringing together enzymologists, clinicians and structural biologists," said Samar Hasnain.
"The synchrotron source at Daresbury has allowed us to investigate the human enzyme and mutants causing the disease, and their structures have provided some important clues for the disease process." ALS affects about 1 in 1000 people, 10% of whom are familial cases and the remaining 90% sporadic, with no apparent link to inheritance.
It is hoped that by understanding the inherited form of ALS scientists may also learn more about the sporadic cases.
Lucie Bruijn, science director and vice president of the ALS Association, said: "The presence of aggregated proteins in neurodegenerative diseases such as Alzheimer's, Hungtington's and ALS is an emerging common theme.
These findings may lead to an understanding of how to disrupt aggregate formation and should these be integral to the disease mechanism, may lead to potential therapeutic approaches."
