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 SOD1G93A 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by a progressive loss of somatic motor neurons, muscle wasting and paralysis
Analysis of P126 control mice showed that the insulin-like growth factor 2 (IGF-2) protein was higher in oculomotor neurons than in hypoglossal and spinal motor neurons (Fig. 1f–i), and remained preferential to oculomotor neurons in P126 symptomatic SOD1G93A mice (Fig. 1j–m), at levels comparable to that seen in control mice (Supplementary Fig. 1a)
Human post mortem analysis revealed that IGF-2 protein was preferential to oculomotor neurons in non-demented control tissues compared to hypoglossal and spinal motor neurons (Fig. 1n–q)
Summary
Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by a progressive loss of somatic motor neurons, muscle wasting and paralysis. An investigation of factors intrinsic to oculomotor neurons in health and disease could reveal mechanisms of neuronal resistance and be the basis for future therapeutic strategies to protect vulnerable motor neurons from degeneration. While the underlying causes of ALS and SMA appear quite distinct, it has been shown that SMN, FUS and TDP-43 can functionally interact, indicating that SMA and ALS share pathways and supporting the view that common mechanisms could be targeted in these genetically distinct diseases[20,21] This is further supported by the loss of spliceosome integrity that has been identified as a critical mechanism common to neurodegeneration in ALS and SMA22. We delivered IGF-2 to SOD1G93A fALS mice in vivo using adeno-associated virus 9 (AAV-9) to study effects on motor performance, life-span and motor neuron survival
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