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

Autor: García-Huerta P; Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Sector B, Second Floor, Faculty of Medicine, University of Chile, Independencia 1027, P.O. Box 70086, Santiago, Chile., Troncoso-Escudero P; Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Sector B, Second Floor, Faculty of Medicine, University of Chile, Independencia 1027, P.O. Box 70086, Santiago, Chile.; Center for Integrative Biology, Faculty of Sciences, University Mayor, Santiago, Chile., Wu D; Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Thiruvalluvan A; Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Cisternas-Olmedo M; Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Center for Integrative Biology, Faculty of Sciences, University Mayor, Santiago, Chile., Henríquez DR; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Department of Cell Biology, Faculty of Sciences, University of Chile, Santiago, Chile., Plate L; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Chana-Cuevas P; Faculty of Medical Sciences, University of Santiago de Chile, Santiago, Chile., Saquel C; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Center for Integrative Biology, Faculty of Sciences, University Mayor, Santiago, Chile., Thielen P; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, 02115, USA., Longo KA; Proteostasis Therapeutics, Cambridge, MA, USA., Geddes BJ; Proteostasis Therapeutics, Cambridge, MA, USA., Lederkremer GZ; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.; George Wise Faculty of Life Sciences, School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Tel Aviv, Israel., Sharma N; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.; George Wise Faculty of Life Sciences, School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Tel Aviv, Israel., Shenkman M; Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.; George Wise Faculty of Life Sciences, School of Molecular Cell Biology and Biotechnology, Tel Aviv University, Tel Aviv, Israel., Naphade S; Buck Institute for Research on Aging, Novato, CA, 94945, USA., Sardi SP; Rare and Neurological Diseases Therapeutic Area, Sanofi, 49 New York Avenue, Framingham, MA, 01701, USA., Spichiger C; Faculty of Sciences, Institute of Biochemistry and Microbiology, University Austral of Chile, Valdivia, Chile., Richter HG; Faculty of Medicine, Institute of Anatomy, Histology and Pathology, University Austral of Chile, Valdivia, Chile., Court FA; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Center for Integrative Biology, Faculty of Sciences, University Mayor, Santiago, Chile.; Buck Institute for Research on Aging, Novato, CA, 94945, USA., Tshilenge KT; Buck Institute for Research on Aging, Novato, CA, 94945, USA., Ellerby LM; Buck Institute for Research on Aging, Novato, CA, 94945, USA., Wiseman RL; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA., Gonzalez-Billault C; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.; Department of Cell Biology, Faculty of Sciences, University of Chile, Santiago, Chile.; Buck Institute for Research on Aging, Novato, CA, 94945, USA., Bergink S; Department of Biomedical Sciences of Cells and Systems, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands., Vidal RL; Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile. rene.vidal@umayor.cl.; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile. rene.vidal@umayor.cl.; Center for Integrative Biology, Faculty of Sciences, University Mayor, Santiago, Chile. rene.vidal@umayor.cl., Hetz C; Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile. chetz@med.uchile.cl.; Center for Geroscience, Brain Health and Metabolism, Santiago, Chile. chetz@med.uchile.cl.; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Sector B, Second Floor, Faculty of Medicine, University of Chile, Independencia 1027, P.O. Box 70086, Santiago, Chile. chetz@med.uchile.cl.; Buck Institute for Research on Aging, Novato, CA, 94945, USA. chetz@med.uchile.cl.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2020 Nov; Vol. 140 (5), pp. 737-764. Date of Electronic Publication: 2020 Jul 08.
DOI: 10.1007/s00401-020-02183-1
Abstrakt: 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.
Databáze: MEDLINE
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