ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation.
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 SOD1(G93A) 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/SOD1(G93A) 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 SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways.
F. M. Kirby Neurobiology Center and Department of Neurology, Children's Hospital, Boston, MA 02115.
Rhona
R
Seijffers
Jiangwen
J
Zhang
Jonathan C
JC
Matthews
Adam
A
Chen
Eric
E
Tamrazian
Olusegun
O
Babaniyi
Martin
M
Selig
Meri
M
Hynynen
Clifford J
CJ
Woolf
Robert H
RH
Brown
D051700:Activating Transcription Factor 3 / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D051379:Mice; D009046:Motor Neurons / Q000473:pathology*; D018482:Muscle, Skeletal / Q000294:innervation*; D013482:Superoxide Dismutase / Q000235:genetics
D051700:Activating Transcription Factor 3; C103002:Atf3 protein, mouse; D013482:Superoxide Dismutase