TY - JOUR
T1 - Molecular investigation of TBP allele length
T2 - A SCA17 cellular model and population study
AU - Reid, Suzanne J.
AU - Rees, Mark I.
AU - Van Roon-Mom, Willeke M.C.
AU - Jones, A. Lesley
AU - MacDonald, Marcy E.
AU - Sutherland, Greg
AU - During, Matthew J.
AU - Faull, Richard L.M.
AU - Owen, Michael J.
AU - Dragunow, Mike
AU - Snell, Russell G.
N1 - Funding Information:
We thank Dr. Don Love for the 100GFP construct, Dr. Kim McGinnis for assistance with filter retardation assay methodology, and Dr. John Pearson for statistical analysis. This study was funded by the Wellcome Trust Fund (UK), the NZ Health Research Council, the NZ Marsden Fund and the Auckland Medical Research Foundation, and the Medical Research Council (UK).
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2003/6
Y1 - 2003/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/0038399741
U2 - 10.1016/S0969-9961(03)00014-7
DO - 10.1016/S0969-9961(03)00014-7
M3 - Article
C2 - 12758065
AN - SCOPUS:0038399741
SN - 0969-9961
VL - 13
SP - 37
EP - 45
JO - Neurobiology of Disease
JF - Neurobiology of Disease
IS - 1
ER -