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Study Discovers How Gene Mutations Cause ALS and Other Brain, Muscle and Bone Diseases

March 3, 2013

As published in the scientific journal Nature, researchers funded by The ALS Association have discovered how mutations in new genes for ALS cause not only that disease but also other diseases of the brain, muscle and bone. These results also reveal the disease pathways involved in ALS due to other genes and may prepare for the development of new treatments to interrupt these processes.

The researchers found that mutations in genes for certain RNA-binding proteins cause them to switch between alternate shapes and aggregate and to promote the same conformational change and aggregation of the normal protein. This behavior has been seen in other neurodegenerative diseases, collectively called prion diseases, including mad cow disease and Creutzfeldt-Jakob disease. In those diseases, this ability leads to spread of the disease throughout the nervous system.

“This discovery may lead us to think more broadly about how ALS progresses within the brain and to ask whether a similar spreading process is occurring,” said Lucie Bruijn, Ph.D., Chief Scientist for The Association.

The team also found that mutations in proteins called heterogeneous ribonuclear proteins (hnRNPs) caused an inherited disease in a small number of families with symptoms of ALS, the frontotemporal dementia, the muscle disease inclusion body myopathy, and the bone disorder Paget’s disease of bone. This cluster of symptoms has recently been recognized as a unique disorder called multisystem proteinopathy. The mutations increased the tendency of the hnRNP proteins to clump together and to induce non-mutated forms of the protein to do so as well. hnRNP proteins normally link to another ALS-associated protein called TDP-43, and the two were found together in the aggregates.

“While these mutations are themselves a very rare cause of ALS, they may provide an important clue about how other forms of ALS spread over time,” Dr. Bruijn said. “Preventing protein aggregation may be a viable therapeutic approach for many forms of ALS.”

The study was led by J. Paul Taylor, M.D., Ph.D., of the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital in Memphis, Tennessee and colleagues from the United States and Europe. These researchers received funding through The ALS Association’s Translational Research Advancing Therapies (TREAT ALS™) program, which funds a diverse portfolio of research at leading institutions all over the world.

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