Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates

Paula García-Huerta, Paulina Troncoso-Escudero, Di Wu, Arun Thiruvalluvan, Marisol Cisternas-Olmedo, Daniel R. Henríquez, Lars Plate, Pedro Chana-Cuevas, Cristian Saquel, Peter Thielen, Kenneth A. Longo, Brad J. Geddes, Gerardo Z. Lederkremer, Neeraj Sharma, Marina Shenkman, Swati Naphade, S. Pablo Sardi, Carlos Spichiger, Hans G. Richter, Felipe A. CourtKizito Tshitoko Tshilenge, Lisa M. Ellerby, R. Luke Wiseman, Christian Gonzalez-Billault, Steven Bergink, Rene L. Vidal*, Claudio Hetz*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington’s disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species.

Original languageEnglish
Pages (from-to)737-764
Number of pages28
JournalActa Neuropathologica
Issue number5
StatePublished - 1 Nov 2020


FundersFunder number
Harvard Brain Tissue Resource CenterNS300
Millennium Institute P09-015-F
Postgraduate Student Research and Innovation Project of Jiangsu ProvinceKYLX15_0558
National Institutes of HealthR01 NS100529
National Institute of Neurological Disorders and StrokeR01NS092829
Fondo Nacional de Desarrollo Científico y Tecnológico1180186
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
China Scholarship Council
Fondo de Fomento al Desarrollo Científico y TecnológicoD11E1007, ID16I10223
Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias15150012
Agencia Nacional de Investigación y Desarrollo


    Dive into the research topics of 'Insulin-like growth factor 2 (IGF2) protects against Huntington’s disease through the extracellular disposal of protein aggregates'. Together they form a unique fingerprint.

    Cite this