Death by polyglutamine: expanding our knowledge

Glutamine Repeats and Neurodegenerative Diseases: Molecular Aspectsedited by P.S. Harper and M. Perutz, Oxford University Press, 2001. £63.50 (312 pages)ISBN 019 850685 6Ten years ago, polyglutamine diseases didn't exist – at least, we didn't know they were there. Five years ago, we were fully aware of their existence but had few clues to disease mechanisms. Today, following a flurry of recent advances, we have answers to many of the mysteries underlying this class of inherited neurodegenerative diseases. We can even begin to speak of the very real possibility of therapies based on an understanding of disease mechanisms. The future looks bright for a field that didn't exist a decade ago.Befitting this rapid advance, the field now has its own book. Glutamine Repeats and Neurodegenerative Disease: Molecular Aspects represents the first definitive volume addressing the molecular mechanisms of polyglutamine diseases. Based on a 1998 scientific meeting sponsored by the Royal Society and organized by the editors, this book is a collection of research-based articles by leading scientists. It is, in a sense, a celebration of scientific advances that occurred in this field in the late 1990s. These advances included both the discovery that protein misfolding is central to disease pathogenesis and the development of powerful animal models that replicate fundamental features of polyglutamine disease.After a succinct, beautifully written introductory chapter on Huntington's disease (HD), the rest of the book is divided into five sections containing twenty chapters. The first section describes insights gained from various animal models, the second focuses on polyglutamine aggregation and toxicity and the third covers cellular and biochemical aspects of huntingtin, the disease protein in HD. These three sections overlap considerably, but that is to be expected when much of the best science in the field crosses traditional disciplinary boundaries. The fourth section, a brief discussion of genomic features of triplet repeat instability, is peripheral to the main themes of the book. The final section covers polyglutamine diseases other than HD (the primary focus of this book) and concludes with an outstanding chapter that draws parallels between ‘polyglutaminopathies’ and two other classes of neurodegenerative proteinopathies, the tauopathies and synucleinopathies. Whereas some chapters are merely truncated versions of research described more completely in the primary literature, many others go well beyond the research articles upon which they are based.What will you get from this book? In one tidy package, a fairly up-to-date snapshot of the current thinking in the field, including controversies and unresolved questions. What, for example, do nuclear inclusions of polyglutamine disease protein tell us about disease mechanisms? And how do we explain neuronal selectivity when the disease proteins are widely expressed?What you will you not get? Several currently ‘hot’ areas in the field are barely covered: for example, the identification of genes and compounds that suppress polyglutamine toxicity; the role of molecular chaperones in modulating disease; and the recognition that transcriptional dysregulation might be important in pathogenesis. The editors shouldn't be blamed for these omissions, however. Rather, it is a byproduct of this field's rapid progress outstripping the speed of publishing a book. Despite its minor shortcomings I am pleased to have this book on my shelf. I suspect that, on a regular basis, it will find its way off that shelf into the hands of students, postdocs or residents who want a quick overview of the field.