Insights into Huntington's disease

Glutamine Repeats and Neurodegenerative Diseases: Molecular Aspectsedited by Peter S. Harper and Max PerutzOxford University Press, 2001. $95 hbk (312 pages) ISBN 0 19 8506856Since the discovery of the gene that is responsible for Huntington's disease (HD) in 1993, there has been a remarkable surge in efforts to study HD and other polyglutamine-repeat diseases. Glutamine Repeats and Neurodegenerative Diseases: Molecular Aspects is a compilation of articles written by active researchers following a Royal Society meeting. It provides an accessible and comprehensive overview of the field, discussing the key discoveries that have contributed to the remarkable progress achieved in HD research. Most of the text describes efforts to understand how the mutant protein causes pathogenesis at the cellular and molecular level.The book covers clinical aspects of the disease, animal models (including mouse and Drosophila), polyglutamine toxicity, biochemical studies and CAG-repeat instability. It also describes diseases arising from repeat expansion in other proteins that have little in common beyond the polyglutamine repeat, including those proteins underlying the spinocerebellar ataxias, dentatorubral pallidoluysian atrophy (DRPLA), Kennedy's disease, as well as polyglutamine repeat expansions in proteins that do not normally cause neurodegenerative disease. A final chapter discusses the role of nerve cell inclusions in neurodegenerative diseases that do not involve polyglutamine repeats. The accompanying illustrations and pictures reinforce the experimental descriptions and are beautifully reproduced.Huntington's disease has emerged as a template for the study of neurodegenerative diseases in general. In common with other triplet-repeat diseases, HD shows anticipation, whereby successive generations display more-severe manifestations or earlier onset of the disease. Primarily, this occurs when the mutant gene is inherited from the father because of large repeat expansions in the germline (potentially through replication slippage mechanisms). There is an inverse correlation of repeat length and age of onset; that is, in general the longer the repeat, the earlier the onset.More model systems have been generated for HD than for any other neurodegenerative disease. Although the biochemical mechanism of HD pathogenesis is not fully understood, the book's contributors discuss working hypotheses. Mouse models expressing different forms of mutant Huntingtin (Htt, the product encoded by the HD gene) under the control of different promoters show that HD is a disease involving ‘gain of function’ or aberrant function.Recently, much attention has focused on the formation of cellular aggregates containing expanded polyglutamine proteins, and many of these experimants are discussed. These aggregates were first described in a transgenic mouse model of HD that demonstrated the formation of nuclear inclusions containing truncated Htt protein and ubiquitin. Amino-terminal fragments of mutant Htt protein have also been found in intranuclear inclusions in neurons and dystrophic neurites of HD brain tissue and in the neuronal processes (neuropil) of both HD-patient and transgenic-mouse brains. In addition, in vitro experiments demonstrate that aggregation is dependent on polyglutamine-repeat length. However, the role of aggregation in disease is far from understood.The potential role of protein–protein interactions and proteolytic processing leading to nuclear localization is also discussed. The first glimpses of an involvement of nuclear transcription factors in HD were presented at this meeting. Htt has been shown to interact with important transcriptional regulatory proteins, such as CREB-binding protein (CBP), TAF130, NCoR and p53. In addition, many of these transcription factors co-localize to the aggregates. From these studies, mechanisms of how Htt might interfere with the normal transcriptional machinery leading to altered gene expression in neurons are evolving. With these new advances in understanding pathogenic mechanisms, therapeutic approaches to treating disease are being developed.Many laboratories that did not study neurodegenerative diseases in the past are now using HD as a model for understanding protein processing and aggregation, protein folding and chaperone function, transcriptional dysregulation, the roles of subcellular organelles in disease, as well as many other cellular processes. In addition, many of the discoveries described, such as the presence of protein aggregates in the nuclei of neurons in mouse models and human brains, have brought unifying themes to the underlying molecular pathology of neurodegenerative diseases from the polyglutamine repeat diseases to Alzhemier's, Pick's and Parkinson's diseases, all of which show some type of aggregation phenomenon.The advances that have occurred since this book was written show the difficulty for any publication of this nature to remain current; for instance, there are now yeast and Caenorhabditis elegans models of HD too new to have been included. Even so, this book is a timely assimilation of a large body of work, and it remains the most comprehensive and up-to-date overview of the field at the molecular and cellular level. Besides being an invaluable reference source, it will continue to stimulate scientific interest and involvement in understanding the consequences of polyglutamine repeat expansion in disease.