Abstract
Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disease caused by polyglutamine expansion within the Atrophin-1 protein. To study the mechanism of this disease and to test potential therapeutic methods, we established Atro-118Q transgenic mice, which express in neurons a mutant human Atrophin-1 protein that contains an expanded stretch of 118 glutamines. Consistent with the results from previous studies on transgenic mice that expressed mutant Atrophin-1 with 65 glutamines, Atro-118Q mice exhibited several neurodegenerative phenotypes that are commonly seen in DRPLA patients, including ataxia, tremors, and other motor defects. Overexpression of wild-type human Atrophin-1 could not rescue the motor and survival defects in Atro-118Q mice, indicating that the mutant protein with polyglutamine expansion does not simply function in a dominant negative manner. Biochemical analysis of Atro-118Q mice revealed hypoacetylation of histone H3 in brain tissues and thus suggested that global gene repression is an underlying mechanism for neurodegeneration in this mouse model. We further show that intraperitoneal administration of sodium butyrate, a histone deacetylase inhibitor, ameliorated the histone acetylation defects, significantly improved motor performance, and extended the average life span of Atro-118Q mice. These results support the hypothesis that transcription deregulation plays an important role in the pathogenesis of polyglutamine expansion diseases and suggest that reversion of transcription repression with small molecules such as sodium butyrate is a feasible approach to treating DRPLA symptoms.
Highlights
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Atro-118Q Transgenic Mice Exhibit Neurodegenerative Phenotypes— To establish a mouse model for Dentatorubral-pallidoluysian atrophy (DRPLA), we used the neuron-specific enolase (NSE) promoter to drive the expression of human atrophin-1 in neurons (Fig. 1A, see “Experimental Procedures”)
Neuropathological analysis showed that widespread nuclear inclusions were observed in various brain regions of Atro-118Q mice, consistent with the pathological feature in DRPLA patients
Summary
Lethality in a Drosophila model of HD [26]. They were successfully used to ameliorate neurodegeneration in mouse models of HD and spinobulbar muscular atrophy [27,28,29]. Two independent groups had established transgenic mice that expressed mutant Atrophin-1 with an expanded stretch of 65 or 78 glutamines [30, 31]. It was demonstrated that polyQ-expanded Atrophin-1 can cause behavioral and neuropathological defects in transgenic mice similar to that seen in DRPLA patients [32]. We used an independently generated DRPLA mouse model to further investigate the disease mechanism and examine the therapeutic potential of SB in treating DRPLA symptoms
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