Abstract

Introduction: Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of a polyglutamine (polyQ) track in the huntingtin protein. We reported that targeting the UPR transcription factor XBP1 delays experimental HD. To identify genes involved in this phenomenon, we performed gene expression profiling of brain tissue from XBP1-KO mice and identified insulin-like growth factor 2 (IGF2) as the major hit. Here we evaluated the possible neuroprotective effects of IGF2 in HD. Material and Methods: We used cellular and preclinical models, human brain and blood samples of HD patients. Results: Cell culture studies revealed that IGF2 decreases intracellular polyQ and mutant huntingtin (mHtt) aggregates. This phenomenon was independent of autophagy or the proteasome pathway. Conversely, we demonstrated that IGF2 signaling enhances the secretion of mHtt by non-conventional mechanisms that involve changes in actin dynamics and exosomes. Administration of IGF2 into the brain of HD mice led to significant decrease in mHtt levels and improved motor performance. Analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction of IGF2 levels. Discussion: This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of mHtt aggregates.