Dr. Ranum’s lab focuses on understanding the fundamental mechanisms and developing therapies for repeat expansion disorders and other neurodegenerative diseases. Her lab discovered Repeat Associated Non-AUG (RAN) translation, a novel process that results in the production and accumulation of toxic proteins in patient tissues, including the brain and central nervous system. Her group has developed several therapeutic strategies to target these proteins. The lab focuses on diseases include amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), the spinocerebellar ataxias (SCAs), myotonic dystrophy (DM), Huntington’s disease (HD) and other genetically unknown neurodegenerative diseases.
- Amyotrophic lateral sclerosis (ALS)
- Frontotemporal dementia (FTD)
- Spinocerebellar ataxias (SCAs)
- Myotonic dystrophy types 1 (DM1) and 2 (DM2)
- Huntington’s disease (HD)
- Genetically unknown neurological diseases
We are always looking for talented graduate students and postdocs to join our team. Please contact Dr. Ranum (firstname.lastname@example.org) to see if positions are available.
Dr. Ranum began her research career in human molecular genetics in 1989 at the University of Minnesota and is currently the Founding Director of the Center for NeuroGenetics and the Kitzman Family Professor of Molecular Genetics and Microbiology at the University of Florida. Over the past 28 years her laboratory has identified the mutations for spinocerebellar ataxia types 5 (SCA5, Nat Genet, 2006) and 8 (SCA8, Nat Genet ,1999), and myotonic dystrophy type 2 (DM2, Science, 2001). and developed mouse models to understand how these and other mutations cause disease and as tools for therapy development.
Many neurodegenerative diseases begin later in life after the nervous system is fully developed. A large group (>50) of these diseases are caused by repeat expansion mutations in which extra copies of short DNA repeats (e.g. CTG•CAG or CCTG•CAGG) cause disease. In 2011, Dr. Ranum’s lab discovered that repeat expansion mutations can undergo a pathological process in which repeat expansion RNAs lacking canonical “AUG” translation-initiation codons serve as templates for the production of toxic proteins, which accumulate in the brain (PNAS, 2011). This paradigm-shifting discovery called repeat associated non-AUG (RAN) translation, is spurring new therapies for diseases caused by microsatellite expansions, including Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), myotonic dystrophy (DM), and a number of spinocerebellar ataxias (SCA) (see Lab Invest, 2019; Ann Rev Neuroscience 2019; Curr Opin Neurol, 2021). In translationally focused therapeutic efforts, the Ranum lab showed that an antibody raised against RAN-translated proteins improved behavior, survival and motor neuron loss in C9orf72 ALS/FTD mice (Neuron, 2020) . This study has paved the way for immunotherapies as a novel strategy to fight RAN protein diseases. Additionally, Dr. Ranum’s group has also shown that metformin, an inexpensive, FDA-approved drug, reduces RAN translation by inhibiting the protein kinase R (PKR) pathway (PNAS, 2020). This study has led to a phase 2 clinical trial (NCT04220021) to test the effects of metformin in C9orf72 ALS patients.
Our lab is currently focused on understanding the molecular mechanisms of RAN translation, the impact of RAN proteins on disease and the development of therapeutic strategies to fight these diseases. The Ranum lab has shown that RAN proteins accumulate in brain tissue from patients diagnosed with SCA8 (EBMO, 2018), ALS (PNAS, 2013) and Huntington’s disease (Neuron, 2015) and is using mouse models for these diseases to better understand the impact of these proteins and to develop therapeutic strategies to target RAN proteins across these disorders. Additionally, the Ranum lab has developed innovative strategies to enrich and identify novel mutations that cause genetically unknown forms of ataxia, ALS and Alzheimer’s disease.
Scientific breakthroughs made in the Ranum laboratory over the years have depended on partnerships with talented students, postdocs and scientific colleagues 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. Our goal is to continue to perform cutting-edge research that will lead to improved diagnoses and treatments for neurological and neuromuscular diseases. A more detailed looked at research in the Ranum lab is outlined below.
Repeat Associated Non-AUG Translation (RAN Translation): In 2011 the Ranum lab reported that the canonical rules of translation do not apply for CTG•CAG repeat expansions and that CAG and CUG expansion transcripts can express homopolymeric expansion proteins in all three frames without an AUG start codon (PNAS, 2011). We showed that this repeat associated non-ATG (RAN) translation is hairpin dependent, occurs without frameshifting or RNA editing and that novel RAN proteins accumulate in both SCA8 and DM1 patient tissues. As expected, our 2011 discovery of RAN translation was highly controversial because it went against the established dogma. For more than two decades the position of the expansion mutation, within or outside an ATG-initiated open reading frame (ORF), provided the framework for research into the molecular consequences of these mutations. RAN proteins have now been reported in 11 different repeat expansion disorders including Huntington’s disease, ALS and frontotemporal dementia (see Curr Opin Neurol, 2021). We are now addressing a number of key questions that our discoveries have raised including: 1) How does this novel translational initiation mechanism work? 2) Are novel repeat expansions in the genome responsible for common diseases including Alzheimer’s disease? 3) Will therapeutic strategies that reduce RAN translation be broadly applicable to a wide range of repeat expansion disorders? 4) Are other repetitive sequences in the highly repetitive human genome translated into proteins and if so, what is their function?
Bidirectional expression of expansion mutations: A second discovery my group made in SCA8 was that the CTG•CAG expansion mutation is bidirectionally transcribed and in addition to CUG expansion transcripts the expansion mutation also produces CAG expansion transcripts that expresses a polyglutamine expansion protein (Nature Genetics, 2006). Both polyGln aggregates and CUG-containing RNA foci accumulate in cerebellar Purkinje cells, which are a primary site of neurodegeneration in the disease. The expression of noncoding CUG expansion transcripts (ataxin 8 opposite strand, ATXN8OS) and the discovery of intranuclear polyglutamine inclusions (Nature Genetics, 2006) and RAN proteins (EMBO, 2018) expressed from ataxin 8 (ATXN8) CAG transcripts suggested SCA8 pathogenesis involves toxic gain of function mechanisms at both the protein and RNA levels. It is now clear that much of the genome and a growing number of expansion loci including the DM1, FMR1, HD, HDL2, SCA7 and C9orf72 ALS/FTD expansion mutations are bidirectionally transcribed raising the possibility that both sense and antisense transcripts contribute to a broad group of neurological diseases (Lab Invest, 2019). We are currently probing the role of sense and antisense transcripts across a number of CAG•CTG expansion disorders including SCA1, 2, 3, 6, 7, 8 and HD.
RNA and RAN mechanisms in SCA8 and DM: In 1999 we discovered that a novel form of ataxia, spinocerebellar ataxia type 8 (SCA8), is caused by a CTG•CAG expansion mutation (Nature Genetics, 1999). In 2001 we showed that a second form of myotonic dystrophy (DM2) is caused by an intronic CCTG•CAGG tetranucleotide expansion (Science, 2001). These discoveries and additional work by others have established that CUG/CCUG expansion RNAs dysregulate alternative splicing pathways. To understand the impact of these expansion mutations on the central nervous system (CNS) we developed SCA8 and DM2 mouse models (Nature Genetics, 2006). Our SCA8 mice showed, for the first time, that CUG expansion transcripts cause RNA gain-of-function effects in the brain and that relatively short expansions (~100 repeats) are sufficient in length to effect these changes (PLoS Genetics, 2009). Recent work from our lab has shown that interruptions in the SCA8 repeat track stabilize RNA structures, increase RAN translation, and increase the likelihood of disease development (EMBO Molecular Medicine, 2021). In myotonic dystrophy type 2, the RNA binding protein muscleblind-like 1 (Mbnl1) sequesters CCUG expansion RNAs in the nucleus, which reduces RAN translation early in disease, but as Mbnl1 proteins are depleted by increased levels of the mutant RNAs, the expansion RNAs are exported to the cytoplasm where they undergo RAN translation (Neuron, 2018). We are currently characterizing a recently generated DM2 and SCA8 BAC mice using a combination of molecular and in vivo optical-imaging strategies to better understand the contributions of RNA and RAN protein effects on neuronal dysfunction and disease. We are also probing the role of ATG-initiated polyglutamine vs. RAN proteins across a number of CAG•CTG expansion disorders including SCA1, 2, 3, 6, 7, 8 and HD.
Novel Human Gene Discovery. Additionally, my laboratory continues to search for novel human disease genes. We are using repeat-enrichment strategies and high-throughput sequencing to identify novel repeat expansion mutations that cause genetically unknown forms of ataxia, amyotrophic lateral sclerosis (ALS), neuropsychiatric and age-related dementias including Alzheimer’s disease. These tools allow us to better understand the genetic causes of often ignored or poorly understood neurologic and neuromuscular diseases. We have collected samples from over 450 families affected by known and unknown genetic diseases with a focus on diseases caused by repeat expansion mutations. Additionally, we have established a network of collaborators across the globe who have provided access to additional samples as needed. We hope that the discovery of novel repeat expansion diseases will lead to a better understanding of the molecular mechanisms of these diseases and to opportunities to develop drugs that work across a large number of repeat expansion disorders.
Therapeutic Efforts. We have pioneered novel approaches to target RAN proteins using passive immunotherapy (Neuron, 2020). Our work has paved the way for immunotherapeutic approaches to fight RAN protein diseases. We have also identified the protein kinase R (PKR) pathway as a novel driver of RAN protein production and have shown that inhibiting PKR decreases RAN protein expression across multiple types of disease-causing repeats (PNAS, 2020). Additionally, we have shown that the FDA approved drug metformin inhibits RAN translation through the PKR pathway (PNAS 2020, comment in PNAS, 2020). This study has led to a phase 2 clinical trial (NCT04220021) to test the effects of metformin in C9orf72 ALS patients. We are currently using cell culture and mouse models to explore the effects of metformin on other repeat expansion disorders. We are currently testing if therapeutic strategies that target RAN proteins and show beneficial effects in one disease will be broadly applicable to other repeat expansion disorders.
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