Interestingly, ectopic expression of Progerin in both WT and HD neurons exacerbated the otherwise non-significant changes in gene expression between these cells, revealing IGF1 and genes involved in neurogenesis and nervous system development as consistently altered in the HD cells.
Here, we analyzed the effect of IGF-1 versus insulin on energy metabolic parameters using striatal cells derived from HD knock-in mice and primary cortical cultures from YAC128 mice.
Insulin and IGF-1 improve mitochondrial function in a PI-3K/Akt-dependent manner and reduce mitochondrial generation of reactive oxygen species in Huntington's disease knock-in striatal cells.
The insulin-like growth factor I (IGF-1)/Akt pathway plays a crucial role in Huntington's disease by phosphorylating the causative protein, polyQ-huntingtin, and abolishing its toxic properties [Humbert et al.(2002)Dev.Cell, 2, 831-837; Rangone et al.(2004)Eur.J.Neurosci., 19, 273-279].
Collectively, our results strongly suggest the involvement of SGK in HD and further imply that IGF-1 downstream signalling is a key transduction pathway that regulates the toxicity of huntingtin.
We provide evidence of reduced IGF-I in HD patients' skeletal muscle that may be a causal factor in the muscle wasting characteristic of this population.