Reversing Neurodegeneration:A Promise Unfolds

mamoto et al. address in their elegantly simple study. Few human ills have seemed as hopelessly intractable They first established a line of mice carrying a transgene as neurodegenerative diseases. Until recently, there has with the tetO bidirectional promoter flanked by a lacZ been little reason for optimism that we might halt the reporter gene and exon 1 of huntingtin (htt) containing degeneration, let alone cure it. But the work of René 94 CAG repeats (HD94). They then crossed these mice Hen and colleagues (Yamamoto et al., 2000), reported with transgenics expressing the tetracycline-regulated in this issue of Cell, shows that it is possible to arrest transactivator (tTA) under the control of the calcium/ neuronal degeneration, at least in early stages of the calmodulin kinase IIa promoter, which have high expresdisease process. By creating a conditional mouse model sion of the transgene in the forebrain (including the striaof Huntington’s disease (HD) that uses the tetracyclinetum, a primary site of HD pathology). Expression of tTA responsive gene system—and thus allows transgene activates expression of both genes flanking the tetO expression to be turned off by oral administration of promoter. Thus, in double transgenic mice both transtetracycline—they discovered that HD-like pathology is genes are constitutively expressed. Doxycycline, a dedependent on continuous expression of a fragment of rivative of tetracycline that readily crosses the blood/ huntingtin with an expanded polyglutamine tract. brain barrier, abolishes expression from the tetO proGlutamine Repeat Diseases: moter by binding to tTA and decreasing its affinity for Progressive Neurodegeneration tetO. Interestingly, in order to obtain the expected yield Huntington’s disease is one of the more familiar memof double transgenic offspring, pregnant females from bers of a group of neurodegenerative disorders known the heterozygote crosses had to be treated with doxycyas triplet repeat diseases. HD and the spinocerebellar cline between gestation day E15 and birth. The explanaataxias (SCAs), among others, result from the expansion tion for this is somewhat unclear. Full-length mutant of an unstable CAG trinucleotide repeat tract in the relehuntingtin with an expanded polyglutamine tract resvant disease gene that causes an expanded stretch of cues the embryonic lethality caused by the absence of glutamines in the resultant proteins (Kaytor and Warren, wild-type huntingtin (Hodgson et al., 1999). The embry1999). The polyglutamine tract itself seems to be the onic lethality seen in the double transgenic mice could source of toxicity: transgenic mice expressing either reflect the greater toxicity expected of the truncated intact protein with an expanded polyglutamine tract or huntingtin with an expanded polyglutamine tract, or it a truncated protein containing the polyglutamine expancould indicate ectopic and/or high expression of hunsion develop neurological phenotypes and neuropatholtingtin due to the calcium/calmodulin kinase IIa proogy reminiscent of the human diseases (see Lin et al., moter. 1999 and references therein). Transgenic mice expressThe double transgenic HD94 mice, in which the bidiing protein with a normal polyglutamine tract (or null rectional transgene expression was activated by the mice lacking the relevant protein function) do not deremoval of doxycycline at birth, revealed high levels of velop the disease phenotype. Although the chief sites both HD94 and lacZ in the striatum, cortex, and hippoof neuropathology vary from one triplet repeat disease campus. A majority of striatal neurons displayed immuto the next, and the function of most of the proteins noreactivity to a huntingtin antibody, showing diffuse remains unknown, this gain-of-function mechanism prenuclear staining as well as nuclear aggregates. By 8 dominates and all the diseases are progressive. The weeks of age, striatal morphological alterations in the longer the repeat tract, the more severe the disease and HD94 mice included a reduced size, reactive gliosis, the earlier its onset. In HD, as in most of the other triplet and a decrease in D1 receptors (a feature seen in HD repeat diseases, the mutant proteins form nuclear agpatients). All of the HD94 mice at this age also showed gregates that have resisted the most strenuous bioa behavioral abnormality common to mouse models of chemical efforts to solubilize them. Even truncated proHD: when suspended by their tails, they clasp their