Artículo de revista
Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates
Fecha
2020Registro en:
Acta Neuropathologica Volumen: 140 Número: 5 Páginas: 737-764 Jul 2020
10.1007/s00401-020-02183-1
Autor
García Huerta, Paula
Troncoso Escudero, Paulina
Wu, Di
Thiruvalluvan, Arun
Cisternas, Marisol
Henríquez, Daniel R.
Plate, Lars
Chana-Cuevas, Pedro
Saquel, Cristian
Thielen, Peter
Longo, Kenneth A.
Geddes, Brad J.
Lederkremer, Gerardo Z.
Sharma, Neeraj
Shenkman, Marina
Naphade, Swati
Sardi, S. Pablo
Spichiger, Carlos
Richter, Hans G.
Court, Felipe A.
Tshilenge, Kizito Tshitoko
Ellerby, Lisa M.
Wiseman, R. Luke
Gonzalez Billault, Christian
Bergink, Steven
Vidal, René L.
Hetz Flores, Claudio
Institución
Resumen
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.