Proteotoxicity of polyglutamine expansion proteins: Cellular mechanisms and their modulation by molecular chaperones

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.