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Authordc.contributor.authorGarcía Huerta, Paula 
Authordc.contributor.authorTroncoso Escudero, Paulina 
Authordc.contributor.authorWu, Di 
Authordc.contributor.authorThiruvalluvan, Arun 
Authordc.contributor.authorCisternas, Marisol 
Authordc.contributor.authorHenríquez, Daniel R. 
Authordc.contributor.authorPlate, Lars 
Authordc.contributor.authorChana-Cuevas, Pedro 
Authordc.contributor.authorSaquel, Cristian 
Authordc.contributor.authorThielen, Peter 
Authordc.contributor.authorLongo, Kenneth A. 
Authordc.contributor.authorGeddes, Brad J. 
Authordc.contributor.authorLederkremer, Gerardo Z. 
Authordc.contributor.authorSharma, Neeraj 
Authordc.contributor.authorShenkman, Marina 
Authordc.contributor.authorNaphade, Swati 
Authordc.contributor.authorSardi, S. Pablo 
Authordc.contributor.authorSpichiger, Carlos 
Authordc.contributor.authorRichter, Hans G. 
Authordc.contributor.authorCourt, Felipe A. 
Authordc.contributor.authorTshilenge, Kizito Tshitoko 
Authordc.contributor.authorEllerby, Lisa M. 
Authordc.contributor.authorWiseman, R. Luke 
Authordc.contributor.authorGonzalez Billault, Christian 
Authordc.contributor.authorBergink, Steven 
Authordc.contributor.authorVidal, René L. 
Authordc.contributor.authorHetz Flores, Claudio
Cita de ítemdc.identifier.citationActa Neuropathologica Volumen: 140 Número: 5 Páginas: 737-764 Jul 2020es_ES
Abstractdc.description.abstractImpaired 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.es_ES
Type of licensedc.rightsAttribution-NonCommercial-NoDerivs 3.0 Chile*
Link to Licensedc.rights.uri*
Sourcedc.sourceActa Neuropathologicaes_ES
Keywordsdc.subjectYAC128 mouse modeles_ES
Keywordsdc.subjectStress-independent activationes_ES
Keywordsdc.subjectMutant huntingtines_ES
Keywordsdc.subjectEr stresses_ES
Keywordsdc.subjectFactor-ii/mannose-6-phosphate receptores_ES
Keywordsdc.subjectGene-expression; Memoryes_ES
Títulodc.titleInsulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregateses_ES
Document typedc.typeArtículo de revistaes_ES
dcterms.accessRightsdcterms.accessRightsAcceso Abierto
Indexationuchile.indexArtículo de publicación ISI
Indexationuchile.indexArtículo de publicación SCOPUS

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Attribution-NonCommercial-NoDerivs 3.0 Chile
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivs 3.0 Chile