Hideki Sakahira and colleagues from Ulrich Hartl’s lab at the Max Planck Institute for Biochemistry, Martinsried, Germany, review the relationship between toxic polyglutamine (polyQ) expansions and the proteasome machinery. Though all PolyQ-expanded proteins are known to be inherently “sticky” and wont to form fibrillary aggregates, the exact mechanism whereby they damage neurons is still speculative. Sakahira focuses on two proposed models for polyQ toxicity. The sequestration/ transcriptional dysregulation model suggests that protofibrils bind and sequester other essential proteins, such as transcription factors, and in this way disrupt cellular function. The second model predicts that polyQ proteins inhibit the proteasome, the large proteolytic apparatus that chops up proteins marked for removal from the cell. This would cause a backlog of misfolded or denatured protein. Chaperones, so named because they help large and hydrophobic proteins fold correctly, may play a crucial role in both models. They could either prevent PolyQ proteins from sequestering essential transcription factors, or keep them in a soluble form that the proteasome can handle.

Nancy Bonini, University of Pennsylvania, reviews how Drosophila has been instrumental in formulating these models. Chaperones such as the heat shock proteins Hsp70 and Hsp40 can alleviate the effects of polyQ-expanded damage to the fly’s eye. This has been shown in fly models of PolyQ diseases, in which expanded human proteins are expressed in the animal’s neurons. Similarly, these chaperones can alleviate symptoms seen in a Parkinson’s model, in which the mutant a-synuclein found in familial forms of the disease is introduced into the fly.-Tom Fagan.

Reference:Sakahira H, Breuer P, Hayer-Hartl MK, Hartl FU. Molecular chaperones as modulators of polyglutamine protein aggregation and toxicity. Proc Natl Acad Sci U S A 2002 Aug 20; (Abstract)

Bonini NM. Chaperoning brain degeneration. Proc Natl Acad Sci U S A 2002 Jul 29; (Abstract)