Human Molecular Genetics Advance Access originally published online on July 30, 2009
Human Molecular Genetics 2009 18(21):4141-4152; doi:10.1093/hmg/ddp363
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Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17
1 Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA 2 Department of Medicine, San Diego School of Medicine, University of California, 9500 Gilman Drive, La Jolla, CA 92093, USA
* To whom correspondence should be addressed at: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA. Tel: +1 4047273290; Fax: +1 4047273949; Email: xli2{at}emory.edu
Received May 10, 2009; Accepted July 27, 2009
TATA binding protein (TBP), a universal transcription factor, is broadly required by nuclear RNA polymerases for the initiation of transcription. TBP contains a polymorphic polyglutamine tract in its N-terminal region, and expansion of this tract leads to spinocerebellar ataxia type 17 (SCA17), one of nine dominantly inherited neurodegenerative diseases caused by polyglutamine expansion in the affected proteins. The expanded polyglutamine proteins are ubiquitously expressed, but cause selective and characteristic neurodegeneration in distinct brain regions in each disease. Unlike many other polyglutamine proteins, whose functions are not yet fully understood, TBP is a well-characterized transcription factor that is restricted to the nucleus. Thus, investigating how mutant TBP mediates neuropathology should help elucidate the mechanisms by which transcriptional dysregulation contributes to neuronal dysfunction and/or neurodegeneration in polyglutamine diseases. To this end, we characterized cellular and mouse models expressing polyQ-expanded TBP. The cell model exhibits characteristic features of neuronal dysfunction, including decreased cell viability and defective neurite outgrowth. We found that the high-affinity nerve growth factor receptor, TrkA, is down-regulated by mutant TBP in cells. Down-regulation of TrkA also occurs in the cerebellum of SCA17 transgenic mice prior to Purkinje cell degeneration. Mutant TBP binds more Sp1, reduces its occupancy of the TrkA promoter and inhibits the activity of the TrkA promoter. These findings suggest that the transcriptional down-regulation of TrkA by mutant TBP contributes to SCA17 pathogenesis.