Dr. Laura P.W. Ranum
Laura P.W. Ranum, Ph.D.
Director of Center for NeuroGenetics
Professor of UF MGM
Phone: (352) 294-5209
Fax: (352) 273-8284
University of Florida
Dept. of Molecular Genetics & Microbiology
2033 Mowry Rd.
Gainesville, FL. 32610
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.
RNA gain-of-function 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 21:379-384). In 2001 we showed that a second form of myotonic dystrophy (DM2) is caused by an intronic CCTG•CAGG tetranucleotide expansion (Science 293:864-867). 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 DM mouse models (Nature Genetics 38:758-769, 2006; and Margolis et al., in preparation). 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 5:e1000600, 2009). We are currently characterizing our DM and SCA8 mice using a combination of molecular and in vivo optical-imaging strategies to determine if specific alternative splicing changes caused by CUG and CCUG expansion transcripts lead to neuronal phenotypes.
Bidirectional expression of CAG•CTG expansion mutations: Our work also led to the novel discovery that the SCA8 expansion mutation is bi-directionally transcribed and expresses expansion transcripts in both the CUG (ataxin 8 opposite strand, ATXN8-OS) and CAG (ataxin 8, ATXN8) expansion transcripts (Nature Genetics 38:758-769, 2006). The ATXN8 transcripts express a nearly pure polyglutamine expansion protein from an ATG-initiated open reading frame (ORF). This was the first demonstration that a microsatellite expansion mutation could be expressed in both directions. Since this report, bidirectional expression has been shown to also occur for many other triplet expansion disorders including DM1, FXTAS, SCA7, HD and HDL2. These results raise the possibility that RNA gain-of-function effects contribute to diseases currently thought to be caused by protein gain-of-function effects and that unrecognized expansion proteins play a role in disorders known to involve RNA gain of function mechanisms. We are currently exploring the potential pathogenic role that bidirectional transcription plays in SCA8 and other microsatellite expansion disorders.
Repeat Associated Non-AUG Translation (RAN-Translation): A major surprise that has recently come out of our work is that the canonical rules of translational initiation do not apply for CAG and CUG expansions and that these repeats express homopolymeric proteins in all three frames without an ATG-initiation codon. We showed this repeat associated non-AUG translation (RAN-translation) depends on RNA structure and repeat length and that RAN-translation occurs in vivo in DM1 and SCA8 (PNAS 108:260-265, 2011). We are now addressing a number of provocative questions that this discovery raises including: 1) How does this novel translational initiation mechanism work? 2) Is RAN-translation a key, previously unrecognized, pathogenic mechanism in neurological disease? 3) Are other repetitive sequences in the genome translated into proteins and if so, what is their function?
Spectrin mutations in SCA5. My lab is also involved in the discovery and characterization of other types of novel gene mutations. In 2006 we showed spinocerebellar ataxia type 5 (SCA5), is caused by mutations in the spectrin beta non-erythrocytic 2 (SPTBN2) gene (Nature Genetics 38:184-90, 2006) which encodes the β-III spectrin protein. We recently developed novel mouse and fly models of SCA5 to better understand how SBTBN2 mutations affect protein function and to model the human disease. Additional studies focus on understanding how mutations in SPTBN2 alter cellular function and cause disease.
Novel Human Gene Discovery. Additionally, my 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, amyotrophic lateral sclerosis (ALS) and neuropsychiatric diseases.
Zu T, Gibbens B, Doty NS, Gomes-Pereira M, Huguet A, Stone MD, Margolis J, Peterson M, Markowski TW, Ingram MA, Nan Z, Forster C, Low WC, Schoser B, Somia NV, Clark HB, Schmechel S, Bitterman PB, Gourdon G, Swanson MS, Moseley M, Ranum LP. (2011) Non-ATG-initiated translation directed by microsatellite expansions. Proc. Natl. Acad. Sci. USA 108(1):260-265.
Lorenzo DN, Li MG, Mische SE, Armbrust KR, Ranum LP, Hays TS. (2010) Spectrin mutations that cause spinocerebellar ataxia type 5 impair axonal transport and induce neurodegeneration in Drosophila. J. Cell Biology 189(1):143-158.
Daughters RS, Tuttle DL, Gao W, Ikeda Y, Moseley ML, Ebner TJ, Swanson MS, Ranum LP. (2009) RNA gain-of-function in spinocerebellar ataxia type 8. PLoS Genet. 5(8):e1000600.
Ikeda Y, Daughters RS, Ranum LP. (2008) Bidirectional expression of the SCA8 expansion mutation: one mutation, two genes. Cerebellum 7(2): 150-158.
Moseley ML, Zu T, Ikeda Y, Gao W, Mosemiller AK, Daughters RS, Chen G, Weatherspoon MR, Clark HB, Ebner TJ, Day JW, Ranum LP. (2006) Bidirectional expression of CUG and CAG expansion transcripts and intranuclear polyglutamine inclusions in spinocerebellar ataxia type 8. Nat. Genet. 38(7): 758-769.
Ikeda Y, Dick KA, Weatherspoon MR, Gincel D, Armbrust KR, Dalton JC, Stevanin G, Dürr A, Zühlke C, Bürk K, Clark HB, Brice A, Rothstein JD, Schut LJ, Day JW, Ranum LP. (2006) Spectrin mutations cause spinocerebellar ataxia type 5. Nat. Genet. 38(2): 184-190.
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