title: Genetic inhibition of JNK3 ameliorates spinal muscular atrophy.
abstract: 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.
authors.affiliation: Center of Emphasis in Neurosciences and Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: Naresh K
authors.initials: NK
authors.lastname: Genabai
authors.affiliation: Center of Emphasis in Neurosciences and Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: Saif
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Center of Emphasis in Neurosciences and Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: Zhanying
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Center of Emphasis in Neurosciences and Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Center of Emphasis in Neurosciences and Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA.
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Gabaldon
authors.affiliation: Center of Emphasis in Neurosciences and Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX 79905, USA laxman.gangwani@ttuhsc.edu.
authors.forename: Laxman
authors.initials: L
authors.lastname: Gangwani
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors / Q000235:genetics*; D009046:Motor Neurons; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D013116:Spinal Cord
chemical_list: D048057:Mitogen-Activated Protein Kinase 10