Heterozygous Igf1r deletion does not ameliorate pathological features associated with polyglutamine-containing huntingtin fragment

•R6/2 and littermate R6/2-Igf1rKO/wt mice show comparable lifespans.•Igf1r haploinsufficiency does not diminish striatal HTT aggregates in R6/2 mice.•R6/2 and R6/2-Igf1rKO/wt mice show similar PI3K and Akt phosphorylation status.

The evolutionarily conserved insulin/IGF-1 signaling pathway has pleiotropic effects on various cellular processes. Hypomorphic alleles of the insulin/IGF-1 receptor enhance catabolic processes as well as stress resistance, which ultimately lead to lifespan extension in invertebrates. Moreover, decreased insulin/IGF-1 signaling promotes the maintenance of protein quality control and suppresses the onset of cellular toxicity caused by aggregate-prone proteins. As loss of protein homeostasis is a feature of many sporadic and inherited forms of neurodegenerative disorders, the pharmacological inhibition of the IGF-1 receptor represents a promising potential therapeutic strategy for currently untreatable neurodegenerative disorders. However, additional studies are required to determine whether this approach is suitable to delay pathology in clinically relevant models of neurodegenerative disorders. Here we show that, in a mouse model of Huntington's disease, heterozygous knockout of the Igf1r does not prevent premature lethality of mice expressing a short fragment of the mutant human huntingtin. Moreover, Igf1r haploinsufficiency does not suppress the formation of huntingtin-containing aggregates. Thus, partial genetic manipulation of the insulin/IGF-1 signaling pathway does not seem sufficient to counteract protein toxicity and extend animal survival.