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3.07.2013

ALS Expert Helps Discover New Genetic Causes for Multi-System Degenerative Disorder

The Miller School’s Michael Benatar, M.D., Ph.D., associate professor of neurology, was part of an international team of researchers that discovered two new genetic causes of a multi-system degenerative disorder that typically affects the brain, muscle and bone, and of amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease. Published March 3 in the journal Nature, their study sheds light on the underlying biology of ALS and new opportunities for therapeutic development.

The study identified mutations in genes for two RNA-binding proteins, known as heterogeneous ribonuclear proteins (hnRNPs). The mutations affect a region of the proteins that researchers call “prion-like domains” due to their similarity to yeast proteins called prions. Importantly, the mutations cause the hnRNP proteins to switch between alternate shapes and to aggregate. Moreover, these mutant proteins also promote conformational change and aggregation of the normal hnRNP protein. Such “prion-like” behavior is encountered in Creutzfeld-Jakob disease and other neurodegenerative diseases.

Benatar, the Walter Bradley Chair in ALS Research at the University of Miami, played a key role in the study, “Prion-like domain mutations in hnRNPs cause multisystem proteinopathy and ALS,” by recognizing that the phenotypic presentation of these mutations includes not only the clinical syndrome known as inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia. (IBMPFD), but also ALS.

A rapidly progressive neurodegenerative disease, ALS primarily affects motor nerves in the brain, brainstem and spinal cord, causing progressive weakness of the arms and legs, as well as of the muscles that control talking, swallowing and breathing. There is no known effective treatment, and death usually ensues within five years.

The study’s senior author, J. Paul Taylor, M.D., Ph.D., an associate member of the Department of Developmental Neurobiology at St. Jude Children’s Research Hospital, and coauthors across the United States and Europe speculate that the normal function of prion-like domains is to assemble RNAs into temporary structures called granules, which are part of the cell’s normal protein production machinery. Granules are normally short-lived and the RNA-binding proteins involved in their formation are recycled. But in cells with mutations in the hnRNP genes, the RNA granules accumulate in the cytoplasm of the cells instead of undergoing normal disassembly.

As a result, the normally highly regulated process of protein aggregation and disaggregation is disrupted, leading to dysregulation of RNA processing and the formation of abnormal protein aggregates that are also characteristic of ALS.

The recognition that mutations in these genes cause ALS as well as the degeneration of brain, muscle and bone, and that the downstream effect of the mutations is the formation of abnormal protein aggregates, led the researchers to redefine this disease entity as Multisystem Proteinopathy.

Their study adds to the growing body of evidence that disrupted RNA processing and abnormal protein aggregation are critical elements at the heart of neurodegenerative diseases such as ALS, and that prion-like behavior of aggregated proteins may be an important mechanism whereby the degenerative process in ALS propagates through the nervous system.

A companion clinical paper authored by Benatar and others,clarifying the association between IBMPFD and ALS will be published in another journal soon..

“These discoveries are highly likely to open up new approaches for therapeutic development for patients with ALS and related neurodegenerative diseases,” Benatar said.

In addition to researchers at St. Jude and UM, other coauthors included researchers at Colorado State University; the Mayo Clinic in Jacksonville, Florida; Brigham and Women’s Hospital and Harvard Medical School; the University of Pennsylvania; the NIH’s National Institute on Aging; the Institute of Psychiatry in London; University Children’s Hospital in Freiburg, Germany; Washington University School of Medicine in St. Louis; Stanford University School of Medicine; the Boston Biomedical Research Institute; and the University of California, Irvine.

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