Potential Therapeutic Strategies

There is currently no effective treatment for polyQ-mediated pathology; however, numerous potential therapeutic targets have emerged from the study of polyQ-dependent pathogenesis. Small molecule screening efforts, carried out in various polyQ model systems, also have identified several interesting candidates (Smith et al. 2001; Tanaka et al. 2004; Zhang et al. 2005; Pollitt et al. 2003). In general, two major strategies, namely, attenuation of polyQ aggregation and inhibition of histone deacetylation, have received considerable attention by investigators in recent years.

Among the multitude of agents capable of modulating polyQ aggregation (Sanchez et al. 2003; Smith et al. 2001; Tanaka et al. 2004; Zhang et al. 2005; Pollitt et al. 2003), molecular chaperones have been the most intensively investigated. There are numerous reports of reduced aggregation in polyQ cell models that overexpress Hsp70 and/or its cochaperone Hsp40 (Cummings et al. 1998; Stenoien et al. 1999; Jana et al. 2000; Kobayashi et al. 2000), although variability between cell types has been observed (Wytten-bach et al. 2000). Genetic manipulation of chaperone levels also can attenuate polyQ aggregation and toxicity in both Caenorhabditis elegans (Satyal et al. 2000) and Drosophila melanogaster (Warrick et al. 1999; Chan et al. 2000; Kazemi-Esfarjani and Benzer 2000; Fernandez-Funez et al. 2000); however, chaperone overexpression in mouse models of different polyQ diseases has not been similarly efficacious. Overexpression of Hsp70 in R6/2 HD mice, a well-characterized transgenic line that expresses htt exon 1 with 150 d(CAG) repeats and displays rapid and pervasive neuronal aggregation (Davies et al. 1997; Li et al. 2001), had little or no effect on both neuropathology and phenotype (Hansson et al. 2003; Hay et al. 2004). Similarly, simultaneous overexpression of Hsp40 and Hsp70 in SCA7 transgenic mice did not prevent NII formation or neuronal cell death (Helmlinger et al. 2004). In a mouse model of SBMA, however, introduction of an Hsp70 transgene substantially improved various phenotypic parameters, including survival rate. Amelioration in the double transgenic mice coincided with a reduction in both aggregated and soluble, mutant androgen receptor in muscle and spinal cord tissue (Adachi et al. 2003). Additionally, mild improvements in neuropathol-ogy and motor function without any change in nuclear aggregation have been reported for SCA1 mice overexpressing Hsp70 (Cummings et al. 2001). Thus, the benefit of elevated levels of molecular chaperones in vivo may depend on the polyQ disease protein. With regard to therapy, activation of the heat shock response by certain drugs may be a practical alternative to genetic manipulation, but this strategy has only been tested in organotypic slice culture (Hay et al. 2004).

The potential for histone deacetylase (HDAC) inhibitors in the treatment of polyQ disease appears promising (Bodai et al. 2003), although limited in vivo data are available at present. HDACs were first implicated in polyQ pathology in a screen for genetic modifiers of SCA1 neurodegeneration. Loss-of-function mutations in two HDAC proteins, namely, Rdp3 and the co-factor Sin3A, suppressed a mutant ataxin-1-induced rough eye phenotype (Fernandez-Funez et al. 2000). Subsequently, administration of the HDAC inhibitors butyrate and suberoylanilide hydroxamic acid (SAHA) was shown to rescue polyQ-dependent neurodegeneration in the fly eye with efficacy comparable to that of Sin3A heterozygosity (i.e., a 50% reduction in Sin3A dose) (Steffan et al. 2001). Similarly, sodium butyrate can ameliorate various disease phenotypes in a mouse model of SBMA (Minamiyama et al. 2004), while SAHA improves motor function in R6/2 HD mice (Hockly et al. 2003). Neither compound has any effect on nuclear localization or aggregation of the respective polyQ disease proteins. Notably, the efficacy of these drugs is tempered by their toxicity, which is considerable outside of a limited dose window (Minamiyama et al. 2004; Hockly et al. 2003).

Paradoxically, a recent report indicates that the antioxidant resveratrol, a component of red wine and an activator of sirtuin deacetylases, can attenuate polyQ-mediated neuronal death. Resveratrol treatment was effective in both a C. elegans HD model, which expressed an N-terminal htt fragment with 128 glutamines, and striatal neurons cultured from HD repeat knockin mice (Parker et al. 2005). It is unclear how this finding can be reconciled with the available data on HDAC inhibitors.

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