Sarkar S et al. (2007) A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum Mol Genet 17: 170–178
A promising treatment approach to Huntington's disease is promotion of autophagy to dispose of aggregate-prone proteins such as mutant huntingtin. Lithium has been previously shown to promote autophagy through inhibition of the enzyme inositol monophosphatase (IMPase). A new study by Sarkar et al. demonstrates, however, that another enzyme inhibited by lithium, glycogen synthase kinase-3β (GSK3β), suppresses autophagy by activating the mammalian target of rapamycin (mTOR). The authors show that this inhibitory effect on autophagy might be counteracted by administering lithium in combination with the mTOR inhibitor sirolimus (rapamycin).
In vitro, treatment with lithium in combination with sirolimus increased the number of autophagosomes more than did either treatment alone (P <0.05), whereas the effect of the combination treatment on mTOR activity was similar to that of sirolimus alone. This finding agrees with previous observations in cell culture that the upregulation of autophagy results from both mTOR inhibition by sirolimus and IMPase inhibition by lithium. Sarkar et al. showed that the activating effect of GSK3β on mTOR was nullified by downstream inhibition of mTOR by sirolimus. Supporting this concept, in a Drosophila model of Huntington's disease, treatment with either lithium or sirolimus alone protected against neurodegeneration compared with control, but the effect of both compounds in combination was significantly greater (P <0.05 vs either treatment alone).
The authors conclude that sirolimus and lithium act through two independent pathways to generate an additive positive effect on autophagy. The study shows clear added benefit from combining these two treatments in cell and animal models of Huntington's disease.
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Rationale for treating Huntington's with a sirolimus and lithium combination. Nat Rev Neurol 4, 60 (2008). https://doi.org/10.1038/ncpneuro0679