Huntington's Disease: Can Mice Lead the Way to Treatment?

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As Published http://dx.doi.org/10.1016/j.neuron.2010.12.035

Publisher Elsevier

Version Final published version

Citable link http://hdl.handle.net/1721.1/84528

Terms of Use Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. Neuron Review

Huntington’s Disease: Can Mice Lead the Way to Treatment?

Zachary R. Crook1 and David Housman1,* 1The David H. Koch Institute for Integrative Cancer Research at MIT, 500 Main Street, Building 76-553, Cambridge, MA 02139, USA *Correspondence: [email protected] DOI 10.1016/j.neuron.2010.12.035

Mouse models for Huntington’s Disease (HD) and HD patients demonstrate motor and behavioral dysfunctions, such as progressive loss of coordination and memory, and share similar transcriptional profiles and striatal neuron atrophy. Clear differences between the mouse and human diseases include almost complete striatal degeneration and rarity of intranuclear inclusions in HD, and the fact that mice expressing full-length mutant huntingtin do not demonstrate a shortened life span characteritstic of HD. While no clinical interven- tions tested in mouse models to date have delayed disease progression, the mouse models provide an invaluable tool for both investigating the underlying pathogenic processes and developing new effective therapies. Inherent differences between humans and mice must be considered in the search for efficacious treatments for HD, but the striking similarities between human HD and mouse models support the view that these models are a biologically relevant system to support the identification and testing of potential clinical therapies.

Introduction tion through aberrant protein-protein interactions. Inclusions Huntington’s disease (HD) is a progressive, fatal neurodegener- containing mHTT, wtHTT, ubiquitin, and many cellular proteins ative disorder characterized by motor, cognitive, behavioral, and (Hoffner and Djian, 2002) are seen in patients and animal models. psychological dysfunction. The cause of HD is an expansion These aggregates are not necessarily toxic, but they are within a trinucleotide poly(CAG) tract in exon 1 of the huntingtin commonly observed wherever mHTT is expressed. That the same (HTT) gene (The Huntington’s Disease Collaborative Research aggregates and cellular toxicity observed in humans are also seen Group, 1993). Age of onset is roughly inversely correlated with in many models, with drastically different time scales (from days in the length of the CAG tract, which causes disease when 39 tissue culture to decades in human HD), accentuates the impor- or more CAG repeats are present (Nørremølle et al., 1993). tance of expression levels and protein context in cellular Affecting approximately 1 in 10,000 people worldwide (Myers pathology. This is particularly evident in the wide variety of pheno- et al., 1993), the most obvious pathology is progressive neurode- typic progression seen in the many mouse models of HD, which is generation, particularly within the striatum (caudate and puta- the subject of this review. men). The massive loss of neurons in this region, normally A mutant HD gene is present in the body of an individual from responsible (among many things) for facilitation of volitional conception. The potential for beneﬁcial therapeutic intervention movement, is believed to lead to the characteristic motor is therefore present throughout the life of an affected individual. dysfunctions of HD, such as uncontrolled limb and trunk move- However, the physiological consequences of the presence of the ments, di