Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS
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Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS. / Allodi, Ilary; Comley, Laura; Nichterwitz, Susanne; Nizzardo, Monica; Simone, Chiara; Benitez, Julio Aguila; Cao, Ming; Corti, Stefania; Hedlund, Eva.
I: Scientific Reports, Bind 6, 25960, 2016.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
Y1 - 2016
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
VL - 6
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
M1 - 25960
ER -
ID: 227431726