title: Molecular investigation of TBP allele length: a SCA17 cellular model and population study.
abstract: Recently, an inherited spinocerebellar ataxia (SCA17) has been attributed to polyglutamine coding expansions within the gene coding for human TATA-box binding protein (TBP). The normal repeat range is 25-42 units with patients having as few as 46 repeats. We undertook a TBP repeat length population study showing its relative stability, skewed distribution, and substantial population specific differences. To investigate the mechanism of neurodegeneration in SCA17 we have developed a cellular model expressing full-length TBP with a range of polyQ expansions. As has been found with other polyQ cellular models, insoluble intracellular inclusions form in a repeat-length-dependent manner. In addition, we have shown that the expanded TBP polyQ tract is able to interact with other overexpressed polyQ-containing proteins. Importantly, overexpression of expanded TBP results in increased Cre-dependent transcriptional activity. As TBP is required for transcription by all RNA polymerases, this may indicate a mechanism for aberrant polyQ gain of function.
authors.affiliation: Department of Molecular Medicine, University of Auckland, Private Bag 92019, Auckland, New Zealand.
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Reid
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
authors.forename: Willeke M C
authors.initials: WM
authors.lastname: van Roon-Mom
authors.forename: A Lesley
authors.initials: AL
authors.lastname: Jones
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.forename: Greg
authors.initials: G
authors.lastname: Sutherland
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
authors.forename: Richard L M
authors.initials: RL
authors.lastname: Faull
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.forename: Mike
authors.initials: M
authors.lastname: Dragunow
authors.forename: Russell G
authors.initials: RG
authors.lastname: Snell
mesh_terms: D000818:Animals; D002460:Cell Line; D005787:Gene Frequency; D017930:Genes, Reporter; D005838:Genotype; D049452:Green Fluorescent Proteins; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D019426:Integrases / Q000378:metabolism; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012995:Solubility; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D013329:Structure-Activity Relationship; D035181:TATA-Box Binding Protein / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics*; D014158:Transcription, Genetic; D014162:Transfection; D019680:Trinucleotide Repeat Expansion / Q000502:physiology*; D018911:Trinucleotide Repeats / Q000235:genetics*; D014764:Viral Proteins / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D008164:Luminescent Proteins; D010455:Peptides; D011993:Recombinant Fusion Proteins; D035181:TATA-Box Binding Protein; D014764:Viral Proteins; D049452:Green Fluorescent Proteins; C097188:polyglutamine; C045073:Cre recombinase; D019426:Integrases