IGF2 prevents dopaminergic neuronal loss and decreases intracellular alpha-synuclein accumulation in Parkinson’s disease models.

Dec 04, 2023

Experts: Javiera Arcos,Felipe Grunenwald,Denisse Sepulveda,Carolina Jerez,Valentina Urbina,Tomas Huerta,Paulina Troncoso-Escudero,Daniel Tirado,Angela Perez,Rodrigo Diaz-Espinoza,Esteban Nova,Ulrich Kubitscheck,Juan Eduardo Rodriguez-Gatica,Claudio Hetz,Jorge Toledo,Pablo Ahumada,Diego Rojas-Rivera,Elisa Martín-Montañez,María Garcia-Fernandez,René L Vidal

Parkinson’s disease (PD) is the second most common late-onset neurodegenerative disease and the predominant cause of movement problems. PD is characterized by motor control impairment by extensive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). This selective dopaminergic neuronal loss is in part triggered by intracellular protein inclusions called Lewy bodies, which are composed mainly of misfolded alpha-synuclein (α-syn) protein. We previously reported insulin-like growth factor 2 (IGF2) as a key protein downregulated in PD patients. Here we demonstrated that IGF2 treatment or IGF2 overexpression reduced the α-syn aggregates and their toxicity by IGF2 receptor (IGF2R) activation in cellular PD models. Also, we observed IGF2 and its interaction with IGF2R enhance the α-syn secretion. To determine the possible IGF2 neuroprotective effect in vivo we used a gene therapy approach in an idiopathic PD model based on α-syn preformed fibrils intracerebral injection. IGF2 gene therapy revealed a significantly preventing of motor impairment in idiopathic PD model. Moreover, IGF2 expression prevents dopaminergic neuronal loss in the SN together with a decrease in α-syn accumulation (phospho-α-syn levels) in the striatum and SN brain region. Furthermore, the IGF2 neuroprotective effect was associated with the prevention of synaptic spines loss in dopaminergic neurons in vivo. The possible mechanism of IGF2 in cell survival effect could be associated with the decrease of the intracellular accumulation of α-syn and the improvement of dopaminergic synaptic function. Our results identify to IGF2 as a relevant factor for the prevention of α-syn toxicity in both in vitro and preclinical PD models.
© 2023. The Author(s).

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ABOUT THE EXPERTS

Javiera Arcos,Felipe Grunenwald,Denisse Sepulveda,Carolina Jerez,Valentina Urbina,Tomas Huerta,Paulina Troncoso-Escudero,Daniel Tirado,Angela Perez,Rodrigo Diaz-Espinoza,Esteban Nova,Ulrich Kubitscheck,Juan Eduardo Rodriguez-Gatica,Claudio Hetz,Jorge Toledo,Pablo Ahumada,Diego Rojas-Rivera,Elisa Martín-Montañez,María Garcia-Fernandez,René L Vidal

Javiera Arcos

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Felipe Grunenwald

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Denisse Sepulveda

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Carolina Jerez

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Valentina Urbina

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Tomas Huerta

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Paulina Troncoso-Escudero

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Molecular Diagnostic and Biomarkers Laboratory, Department of Pathology, Faculty of Medicine Clínica Alemana, Universidad del Desarrollo, Santiago, Chile.

Daniel Tirado

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Escuela de Tecnología Médica, Universidad Mayor, Santiago, Chile.

Angela Perez

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Escuela de Tecnología Médica, Universidad Mayor, Santiago, Chile.

Rodrigo Diaz-Espinoza

Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile.

Esteban Nova

Departamento de Química, Facultad de Ciencias Naturales, Matemáticas y Medio Ambiente, Universidad Tecnológica Metropolitana, Santiago, Chile.

Ulrich Kubitscheck

Clausius Institute of Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany.

Juan Eduardo Rodriguez-Gatica

Clausius Institute of Physical and Theoretical Chemistry, University of Bonn, Bonn, Germany.

Claudio Hetz

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.

Jorge Toledo

Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.

Pablo Ahumada

Center for Integrative Biology, Universidad Mayor, Santiago, Chile.

Diego Rojas-Rivera

Escuela de Tecnología Médica, Universidad Mayor, Santiago, Chile.

Escuela de Biotecnología, Universidad Mayor, Santiago, Chile.

Center for Biomedicine, Universidad Mayor, Santiago, Chile.

Elisa Martín-Montañez

Department of Pharmacology, Faculty of Medicine, Biomedical Research Institute of Malaga, University of Malaga, Malaga, Spain.

María Garcia-Fernandez

Department of Human Physiology, Faculty of Medicine, Biomedical Research Institute of Malaga, University of Malaga, Malaga, Spain.

René L Vidal

Center for Integrative Biology, Universidad Mayor, Santiago, Chile. rene.vidal@umayor.cl.

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.

Escuela de Tecnología Médica, Universidad Mayor, Santiago, Chile. rene.vidal@umayor.cl.

Escuela de Biotecnología, Universidad Mayor, Santiago, Chile. rene.vidal@umayor.cl.