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Behrends, Christian (2007): Proteotoxicity of polyglutamine expansion proteins: Cellular mechanisms and their modulation by molecular chaperones. Dissertation, LMU München: Faculty of Chemistry and Pharmacy
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Abstract

Proteins are central to all biological processes. To become functionally active, newly synthesized protein chains must fold into unique three-dimensional conformations. A group of proteins, known as molecular chaperones, are essential for protein folding to occur with high efficiency in cells. Their main role is to prevent off-pathway reactions during folding that lead to misfolding and aggregation. A number of human diseases are known to result from aberrant folding reactions. The formation of insoluble protein aggregates in neurons is a hallmark of neurodegenerative diseases including Huntington’s disease (HD). These disorders are though to result from the acquisition of dominant, toxic functions of misfolded proteins. HD is caused by a CAG trinucleotide expansion that results in the expansion of a polyglutamine (polyQ) tract in the protein Huntingtin (Htt). The disorder is characterized by a progressive loss of specific neurons and the formation of inclusions containing aggregated Htt. Aggregate formation is causally linked to the progressive HD neuropathology, though it is not clear whether large insoluble, fibrillar structures or smaller assemblies of Htt are the toxic agents. Toxicity could arise from the recruitment of other polyQ-containing proteins, i.e. transcription factors, into the inclusions resulting in a loss of their normal cellular functions. Here, soluble Htt oligomers have been found to accumulate in the nucleus and to inhibit the function of the transcription factors TBP and CBP in cells. Aberrant interaction of toxic Htt with the benign polyQ repeat of TBP structurally destabilized the transcription factor, independent of the formation of insoluble coaggregates and caused transcriptional dysregulation. Chaperones of the Hsp70 family protect against this deactivation by modulating the conformation of Htt. This protective effect of Hsp70 was found to be based on a cooperation between Hsp70 and the chaperonin TRiC. Both chaperone systems cooperate in eliminating toxic polyQ oligomers, which may resemble the potentially pathogenic, prefibrillar states of other amyloidogenic disease proteins, and in stabilizing mutant Htt in a soluble, oligomeric state that is not associated with toxicity. TRiC and Hsp70 appear to be part of an effective chaperone network preventing the formation of harmful, amyloidogenic proteins species. They act synergistically on Htt, reminiscent of their sequential action in assisting the folding of newly-synthesized proteins.