London: Researchers have linked newly discovered gene mutations to some cases of the progressive fatal neurological disease amyotrophic lateral sclerosis (ALS), which is also known as Lou Gehrig’s disease.Shedding light on how ALS destroys the cells and leads to paralysis, the researchers found that mutations in this gene affect the structure and growth of nerve cells.ALS attacks motor neurons, the nerve cells responsible for controlling muscles.People with ALS experience such early symptoms as limb weakness or swallowing difficulties.In most people, the disease leads to death three to five years after symptoms develop, usually as a result of respiratory failure.Scientists at the University of Massachusetts Medical School, Worcester, collaborated with international ALS researchers to search for gene mutations in two large families with an inherited form of ALS.The researchers used a technique to decode only the protein-encoding portions of DNA, known as the exome, allowing an efficient yet thorough search of the DNA regions most likely to contain disease-causing mutations.This deep sequencing of the exome led to the identification of several different mutations in the gene for profilin (PFN1) which were present only in the family members that developed ALS.Further investigations of 272 other familial ALS cases across the world showed that profilin mutations were also found in a small subset (about 1 to 2 percent) of the familial ALS cases studied.The protein profilin is a key part of the creation and remodelling of a nerve cell’s scaffolding or cytoskeleton.In fly models, disrupting profilin stunts the growth of axons – the long cell projections used to relay signals from one neuron to the next or from motor neurons to muscle cells.After identifying the PFN1 mutations in ALS patients, the researchers demonstrated that these mutations inhibited axon growth in laboratory-grown motor neurons as well.They also found that mutant profilin accumulated in clumps in neural cells, as has been seen for other abnormal proteins associated with ALS, Parkinson’s and Alzheimer’s.Neural cells with PFN1 mutations also contained clumps of a protein known as TDP-43. Clumps of abnormal TDP-43 are found in most cases of ALS, further linking profilin to known ALS mechanisms.“ALS is a late-onset, rapidly progressive disease. Unless you’ve been following a family for decades, it is hard to get DNA samples to study,” John Landers, associate professor at the University of Massachusetts Medical School, said.“We were very fortunate to obtain the DNA samples with the help of our research collaborators and the affected families,” he said.The study has been published online in Nature.
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