title: Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.
abstract: The fatal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons leading to muscle wasting and paralysis. However, motor neurons in the oculomotor nucleus, controlling eye movement, are for unknown reasons spared. We found that insulin-like growth factor 2 (IGF-2) was maintained in oculomotor neurons in ALS and thus could play a role in oculomotor resistance in this disease. We also showed that IGF-1 receptor (IGF-1R), which mediates survival pathways upon IGF binding, was highly expressed in oculomotor neurons and on extraocular muscle endplate. The addition of IGF-2 induced Akt phosphorylation, glycogen synthase kinase-3β phosphorylation and β-catenin levels while protecting ALS patient motor neurons. IGF-2 also rescued motor neurons derived from spinal muscular atrophy (SMA) patients from degeneration. Finally, AAV9::IGF-2 delivery to muscles of SOD1(G93A) ALS mice extended life-span by 10%, while preserving motor neurons and inducing motor axon regeneration. Thus, our studies demonstrate that oculomotor-specific expression can be utilized to identify candidates that protect vulnerable motor neurons from degeneration.
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: Ilary
authors.initials: I
authors.lastname: Allodi
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: Laura
authors.initials: L
authors.lastname: Comley
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Nichterwitz
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Istituto Di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Istituto Di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Simone
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: Julio Aguila
authors.initials: JA
authors.lastname: Benitez
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: Ming
authors.initials: M
authors.lastname: Cao
authors.affiliation: Dino Ferrari Center, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, Istituto Di Ricovero e Cura a Carattere Scientifico Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan 20122, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
authors.affiliation: Department of Neuroscience, Karolinska Institutet, Retzius v. 8, 171 77 Stockholm, Sweden.
authors.forename: Eva
authors.initials: E
authors.lastname: Hedlund
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D009802:Oculomotor Nerve / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation; D065840:Protective Factors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: C000597236:IGF1R protein, human; C035170:IGF2 protein, human; D017451:Receptors, Somatomedin; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II; D017526:Receptor, IGF Type 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt