Many neurodegenerative diseases begin later in life after the nervous system is fully developed. A major step towards a better understanding of neurodegenerative diseases was made with the discovery that microsatellite repeat expansions are responsible for a large group (>30) of these diseases. In these disorders, extra copies of short DNA repeats (e.g. CTG•CAG or CCTG•CAGG) cause disease. In general, these mutations are thought to cause disease by protein loss-of-function, protein gain-of-function or by RNA gain of function mechanisms. My group uses human genetics to define the molecular causes of neurological disorders and mouse models to understand how these mutations cause neurons in the brain to die.
Current research in the Ranum lab focuses on the role of Repeat Associated Non-ATG (RAN) translation, RNA gain of function and protein gain of function in repeat expansion disorders including amyotrophic lateral sclerosis (ALS), spinocerebellar ataxia (SCA) types 5 and 8, myotonic dystrophy (DM) types 1 and 2 and Huntington’s disease (HD). We are investigating the mechanism by which RAN translation occurs in these diseases and the toxic effects of RAN proteins on the brain and other organs. We have shown that RAN proteins accumulate in brain tissue from patients diagnosed with SCA8, ALS and Huntington’s disease and are using mouse models of these diseases to better understand the impact of these proteins and to develop therapeutic strategies. Additionally, the Ranum laboratory continues to search for novel human disease genes. We are using high-throughput sequencing strategies to look for single-gene mutations that cause novel forms of ataxia, ALS and neuropsychiatric diseases. Because RAN translation has now been shown to occur across multiple diseases, and greater than 30 diseases are caused by repeat expansion mutations, these studies are likely to contribute to the understanding and development of urgently needed therapies for a large category of diseases. Scientific breakthroughs made in the Ranum laboratory over the years have depended on partnerships with talented scientific colleagues and students and with members of the community that have participated in our research studies. Although there is much work that remains, scientific advances have dramatically increased opportunities for drug development and clinical trials. The goal of the Ranum laboratory is to perform cutting edge research that will lead to improvements in diagnosis and treatments for neurological and neuromuscular disease.