Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS

TY - JOUR

T1 - Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS

AU - Allodi, Ilary

AU - Comley, Laura

AU - Nichterwitz, Susanne

AU - Nizzardo, Monica

AU - Simone, Chiara

AU - Benitez, Julio Aguila

AU - Cao, Ming

AU - Corti, Stefania

AU - Hedlund, Eva

PY - 2016/5/16

Y1 - 2016/5/16

N2 - 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.

AB - 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.

KW - Amyotrophic Lateral Sclerosis/genetics

KW - Animals

KW - Cells, Cultured

KW - Disease Models, Animal

KW - Female

KW - Glycogen Synthase Kinase 3 beta/metabolism

KW - HEK293 Cells

KW - Humans

KW - Induced Pluripotent Stem Cells

KW - Insulin-Like Growth Factor II/genetics

KW - Male

KW - Mice

KW - Oculomotor Nerve/cytology

KW - Phosphorylation

KW - Protective Factors

KW - Proto-Oncogene Proteins c-akt/metabolism

KW - Receptors, Somatomedin/metabolism

KW - beta Catenin/metabolism

U2 - 10.1038/srep25960

DO - 10.1038/srep25960

M3 - Journal article

C2 - 27180807

SN - 2045-2322

VL - 6

JO - Scientific Reports

JF - Scientific Reports

M1 - 25960

ER -