Newest ALS Gene Impairs Axon Growth
A newly discovered ALS gene points to defects in axon growth as one cause of the disease. Mutations in the gene, called profilin 1 (PFN1), are responsible for 1% to 2% of familial ALS, according to the new study.
PFN1 helps link individual actin proteins to form actin filaments. Actin is an important structural protein within motor neurons. Actin filaments are fibers that provide structure within axons, the long outgrowths of motor neurons. Growth of actin filaments is necessary for growth of the axons themselves.
An international research team, led by John Landers, Ph.D., of the University of Massachusetts Medical School, performed whole-exome sequencing on DNA samples from two large families with dominantly inherited ALS. Other ALS genes had been ruled out in these families. They found two different mutations in the PFN1 gene, located on chromosome 17. Sequencing of PFN1 in 272 additional familial ALS patients with no known genetic cause revealed five more cases.
“This discovery provides us with another important clue that growth of axons is impaired in ALS,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D. “This is especially significant because it may provide us with a tool to study failure of axonal growth in ALS and to determine if drugs targeted to this process may be beneficial for patients with the disease.”
In cell culture, non-mutant PFN1 was diffused throughout the cytoplasm, while mutant PFN1 was localized in aggregates that also contained TDP-43, another ALS-linked protein. PFN1 was not found in aggregates from patients with sporadic ALS, likely ruling out its involvement in that form of the disease.
The PFN1 mutations identified were all close to the actin-binding site on the protein, and four of the five mutations discovered impaired the protein’s ability to bind actin. Three of those led to decreased growth of axons.
PFN1 also interacts with the ALS gene VCP, as well as the genes responsible for two other neurodegenerative diseases, Huntington’s disease and spinal muscular atrophy.
"We are tremendously excited because these studies inform us about a new mechanism for the cause of ALS,” said Robert Brown, M.D., Ph.D. “Importantly, this molecular pathway, which involves disturbances of nerve growth and repair, provides fresh ideas about how to treat this terrible disease. It is also gratifying to finally know what has triggered ALS in a set of large families that we have studied for many years; Dr. John Landers’ efforts in this project were pivotal. We are also extremely grateful for The ALS Association’s support over the years for genetic studies similar to these and look forward to working in partnership with The ALS Association, P2ALS and Therapy Alliance to make a significant commitment to advancing therapies for ALS and in particular gene silencing approaches for ALS.”
For more information about this research, visit http://www.ncbi.nlm.nih.gov/pubmed/22801503.
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