Genetic inhibition of JNK3 ameliorates spinal muscular atrophy

Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecu...

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Bibliographic Details
Published in:Human molecular genetics 2015-12, Vol.24 (24), p.6986-7004
Main Authors: Genabai, Naresh K, Ahmad, Saif, Zhang, Zhanying, Jiang, Xiaoting, Gabaldon, Cynthia A, Gangwani, Laxman
Format: Article
Language:English
Subjects:
Animals
Cells, Cultured
Disease Models, Animal
Female
Humans
Infant
Infant, Newborn
Male
MAP Kinase Signaling System - genetics
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 10 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 10 - genetics
Motor Neurons
Muscular Atrophy, Spinal - genetics
Muscular Atrophy, Spinal - metabolism
Muscular Atrophy, Spinal - therapy
Spinal Cord
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Summary:Mutation of the Survival Motor Neuron 1 (SMN1) gene causes spinal muscular atrophy (SMA), an autosomal recessive neurodegenerative disorder that occurs in early childhood. Degeneration of spinal motor neurons caused by SMN deficiency results in progressive muscle atrophy and death in SMA. The molecular mechanism underlying neurodegeneration in SMA is unknown. No treatment is available to prevent neurodegeneration and reduce the burden of illness in SMA. We report that the c-Jun NH2-terminal kinase (JNK) signaling pathway mediates neurodegeneration in SMA. The neuron-specific isoform JNK3 is required for neuron degeneration caused by SMN deficiency. JNK3 deficiency reduces degeneration of cultured neurons caused by low levels of SMN. Genetic inhibition of JNK pathway in vivo by Jnk3 knockout results in amelioration of SMA phenotype. JNK3 deficiency prevents the loss of spinal cord motor neurons, reduces muscle degeneration, improves muscle fiber thickness and muscle growth, improves motor function and overall growth and increases lifespan of mice with SMA that shows a systemic rescue of phenotype by a SMN-independent mechanism. JNK3 represents a potential (non-SMN) therapeutic target for the treatment of SMA.
ISSN:0964-6906
1460-2083
DOI:10.1093/hmg/ddv401