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1.
Sci Transl Med ; 13(578)2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504650

RESUMO

Gene replacement and pre-mRNA splicing modifier therapies represent breakthrough gene targeting treatments for the neuromuscular disease spinal muscular atrophy (SMA), but mechanisms underlying variable efficacy of treatment are incompletely understood. Our examination of severe infantile onset human SMA tissues obtained at expedited autopsy revealed persistence of developmentally immature motor neuron axons, many of which are actively degenerating. We identified similar features in a mouse model of severe SMA, in which impaired radial growth and Schwann cell ensheathment of motor axons began during embryogenesis and resulted in reduced acquisition of myelinated axons that impeded motor axon function neonatally. Axons that failed to ensheath degenerated rapidly postnatally, specifically releasing neurofilament light chain protein into the blood. Genetic restoration of survival motor neuron protein (SMN) expression in mouse motor neurons, but not in Schwann cells or muscle, improved SMA motor axon development and maintenance. Treatment with small-molecule SMN2 splice modifiers beginning immediately after birth in mice increased radial growth of the already myelinated axons, but in utero treatment was required to restore axonal growth and associated maturation, prevent subsequent neonatal axon degeneration, and enhance motor axon function. Together, these data reveal a cellular basis for the fulminant neonatal worsening of patients with infantile onset SMA and identify a temporal window for more effective treatment. These findings suggest that minimizing treatment delay is critical to achieve optimal therapeutic efficacy.


Assuntos
Atrofia Muscular Espinal , Animais , Axônios , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Transgênicos , Neurônios Motores , Atrofia Muscular Espinal/terapia , Proteína 1 de Sobrevivência do Neurônio Motor/genética
2.
Hum Mol Genet ; 28(19): 3282-3292, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31272106

RESUMO

A pathological hallmark of spinal muscular atrophy (SMA) is severe motor neuron (MN) loss, which results in muscle weakness and often infantile or childhood mortality. Although it is well established that deficient expression of survival motor neuron (SMN) protein causes SMA, the molecular pathways that execute MN cell death are poorly defined. The c-Jun NH2-terminal kinases (JNKs) are stress-activated kinases with multiple substrates including c-Jun, which can be activated during neuronal injury and neurodegenerative disease leading to neuronal apoptosis. Recently, increased JNK-c-Jun signaling was reported in SMA raising the possibility that JNK inhibitors could be a novel treatment for this disease. We examined JNK-c-Jun activity in SMA mouse and human cultured cells and tissues. Anisomycin treatment of human SMA fibroblasts and sciatic nerve ligation in SMA mice provoked robust phosphorylated-c-Jun (p-c-Jun) expression indicating that SMN-deficiency does not prevent activation of the stress-induced JNK-c-Jun signaling pathway. Despite retained capacity to activate JNK-c-Jun, we observed no basal increase of p-c-Jun levels in SMA compared to control cultured cells, human or mouse spinal cord tissues, or mouse MNs during the period of MN loss in severe SMA model mice. In both controls and SMA, ~50% of α-MN nuclei express p-c-Jun with decreasing expression during the early postnatal period. Together these studies reveal no evidence of stress-activated JNK-c-Jun signaling in MNs of SMA mice or human tissues, but do highlight the important role of JNK-c-Jun activity during normal MN development raising caution about JNK antagonism in this pediatric neuromuscular disease.


Assuntos
Anisomicina/farmacologia , Atrofia Muscular Espinal/metabolismo , Proteínas Proto-Oncogênicas c-jun/metabolismo , Medula Espinal/citologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Feminino , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , Fosforilação , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo
3.
Neuron ; 93(1): 66-79, 2017 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-28017471

RESUMO

The neuromuscular disorder spinal muscular atrophy (SMA), the most common inherited killer of infants, is caused by insufficient expression of survival motor neuron (SMN) protein. SMA therapeutics development efforts have focused on identifying strategies to increase SMN expression. We identified a long non-coding RNA (lncRNA) that arises from the antisense strand of SMN, SMN-AS1, which is enriched in neurons and transcriptionally represses SMN expression by recruiting the epigenetic Polycomb repressive complex-2. Targeted degradation of SMN-AS1 with antisense oligonucleotides (ASOs) increases SMN expression in patient-derived cells, cultured neurons, and the mouse central nervous system. SMN-AS1 ASOs delivered together with SMN2 splice-switching oligonucleotides additively increase SMN expression and improve survival of severe SMA mice. This study is the first proof of concept that targeting a lncRNA to transcriptionally activate SMN2 can be combined with SMN2 splicing modification to ameliorate SMA and demonstrates the promise of combinatorial ASOs for the treatment of neurogenetic disorders.


Assuntos
Regulação da Expressão Gênica , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/genética , RNA Antissenso/genética , RNA Longo não Codificante/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Animais , Western Blotting , Células Cultivadas , Córtex Cerebral/citologia , Imunoprecipitação da Cromatina , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas , Camundongos , Atrofia Muscular Espinal/metabolismo , Neurônios/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Complexo Repressor Polycomb 2/metabolismo , Regiões Promotoras Genéticas , Splicing de RNA , RNA Antissenso/efeitos dos fármacos , RNA Antissenso/metabolismo , RNA Longo não Codificante/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismo , Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo
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