Study identifies how new ALS gene mutations cause other diseases of the brain, muscle and bone

The ALS AssociationMar 4 2013

Researchers supported by The ALS Association have discovered how mutations in new amyotrophic lateral sclerosis (ALS) genes cause not only ALS but also other diseases of the brain, muscle and bone. The results also shed light on the disease pathways of ALS due to other genes and may set the stage for development of new treatments to interrupt these processes. The study was published in the journal Nature.

ALS, also known as Lou Gehrig 's Disease, is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. The disease robs people of the ability to walk, to talk and even blink an eye. It traps them inside a body they no longer can control and ultimately prevents them from breathing as it takes their life.  There is no known cause of the disease, although military veterans are approximately twice as likely to develop ALS as the general population.

The research 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, along with colleagues from elsewhere in the United States and Europe. They 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.

The abovementioned researchers discovered 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."