The HD protein deactivates the transcription factor TBP

This basic research study advances our knowledge about transcription factors in Huntington?s Disease and about the role of chaperones. It has been known since 2001 that the HD protein interferes with gene transcription by interacting with and entangling CBP, a protein that turns on genes needed for cell survival. This study looks at TBP, a different protein that is also involved in transcription and finds that HD protein fragments get into the nucleus of the cell and inactivate TBP. The fragments bind with an otherwise harmless polyglutamine stretch of TBP and destabilize it, contributing to cell dysfunction and death. Interestingly, it is the soluable fragments and not the aggregates which inactivate TBP. The researchers learned that the interaction between the fragments and TBP is dependent upon a rapid structural rearrangement (or conformational change) of the protein which occurs during fragmentation. The protein compacts and quickly begins interacting with and deactivating TBP.

It?s also been known since 1999 that a chaperone, the heat shock protein 70 will arrest neurodegeneration in fruitfly models. However, the exact mechanism by which this happens was not known. This study shows that HSP 70 and its cofactor HSP 40 will interfere with the conformational changes and thereby inhibit the deactivation to TBP.

It seems likely that neurons have similar defense mechanisms. Heat shock proteins got their name because they are produced when cells are stressed by heat or toxins; however, they have a maintenance role in cells as well, helping newly made proteins to fold properly (their chaperone function) and carrying old ones off for degradation. The researchers reason that the aging process could explain why HD is a midlife disease; as the cell ages, its defense mechanisms might become less efficient in dealing with the mutant huntingtin?s protein.

New Insights into the Huntington?s Disease Process
Cellular Toxicity of Polyglutamine Expansion Proteins: Mechanism of Transcription Factor Deactivation.

Gregor Schaffar, Peter Breuer, Raina Boteva, Christian Behrends, Nikolay Tzvetkov, Nadine Strippel, Hideki Sakahira Katja Siegers, Manajit Hayer-Hartl, and F. Ulrich Hartl.

The expression of polyglutamine-expanded mutant proteins in Huntington's disease and other neurodegenerative disorders is associated with the formation of intraneural inclusions. These aggregates could potentially cause cellular toxicity by sequestering essential proteins possessing normal polyQ repeats, including the transcription factors TBP and CBP. We show, in vitro and in cells, that monomers or small soluble oligomers of huntingtin exon1 accumulate in the nucleus and inhibit the function of TBP in a polyQ-dependent manner. FRET experiments indicate that these toxic forms are generated through a conformational rearrangement in huntingtin. Interaction of toxic huntingtin with the benign polyQ repeat of TBP structurally destabilizes the transcription factor, independent of the formation of insoluble coaggregates. Hsp70/Hsp40 chaperones interfere with the conformational change in mutant huntingtin and inhibit the deactivation of TBP. These results outline a molecular mechanism of cellular toxicity in polyQ disease and can explain the beneficial effects of molecular chaperones.

Molecular Cell, Vol 15, 95-105, 2 July 2004