ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation

Significance This study reports on the beneficial effects of forcing high expression of the transcription factor activating transcription factor 3 (ATF3) in ALS. ALS is a noncurable adult-onset disease that attacks motor neurons, resulting in paralysis and death. ATF3 overexpression in motor neurons in an ALS mouse model modifies gene expression and drives the neurons into a prosurvival and proregenerative state, increasing motor neuron survival and maintaining axonal connection with muscle by promoting axonal sprouting. ATF3 overexpression results in markedly improved muscle strength and function and delayed disease onset but only slightly increased lifespan. Molecular mechanisms that promote axonal sprouting could substantially improve quality of life in ALS, although additional approaches will be required to overcome progressive motor neuron deterioration. ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1G93A ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1G93A mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth-promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1G93A mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.

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