I have discussed Progeria before. This is a most unfortunate inherited disease in which children appear to age prematurely. They often die by the age of 13 due to atherosclerosis (heart disease). More information can be found at the web page of the Progeria Research Foundation (http://www.progeriaresearch.org/index.shtml ), which has its own interesting history and is a major force in Progeria research. A recent scientific publication listed at http://www.progeriaresearch.org/index.shtml shows the link between a modification of the protein lamin A and a cholesterol precursor, farnesyl phrophosphate. The chemical structure is shown below.
Genetic studies have previously shown that a mutation in the lamin A gene is responsible for this disease. Lamin A is a cellular structural protein. The mutated form causes aberrant nuclear morphology and probably other biochemical dysfunctions. After the lamin A protein has been synthesized in the cell it is modified by the addition of a farnesyl moiety and methylation. A section of the protein containing these modifications is removed by the action of an enzyme (Zmpste24) that acts at a specific site in the lamin A protein. The Progeria mutation eliminates the region of lamin A containing the enzyme binding site so that the enzyme can’t remove the modified portion of lamin A. This lack of sequence specific proteolysis results in a lamin A with the farnesyl still attached. Even in the presence of normal lamin A, the aberrant form containing farnesyl will cause nuclear deformities and the symptoms of Progeria. It is interesting that farnesyl is also implicated in osteoporosis and cancer. A drug (Tipifarnib) that inhibits the enzyme farnesyl transferase keeping farnesyl off proteins such as lamin A is in phase III clinical trials (http://www.clinicaltrials.gov/ct/show/nct00093418 ) as a treatment for certain types of leukemia.
Will such a drug be able to cure or reduce the symptoms of Progeria?
Could this drug even slow down normal aging? Stay tuned.
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