Active Transport of the Survival Motor Neuron Protein and the Role of Exon-7 in Cytoplasmic Localization

Zhang, Honglai L.; Pan, Feng; Hong, Daewha; Shenoy, Shailesh M.; Singer, Robert H.; Bassell, Gary J.

doi:10.1523/jneurosci.23-16-06627.2003

Cited by 250 publications

(267 citation statements)

References 45 publications

Supporting

Mentioning

243

Contrasting

Unclassified

Order By: Relevance

“…These assembled snRNPs can then catalyze splicing on translocation to the nucleus. Several groups have suggested a function for SMN beyond a role in splicing, in the assembly of axonal granules and mRNA transport within axons (16)(17)(18). Although this may partially explain the neuronal bias of SMA pathology, conclusive evidence of how SMNdependent axonal transport contributes specifically to the SMA motor neuron phenotype remains to be determined.…”

Section: Significancementioning

confidence: 99%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

111

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease, is the leading monogenic cause of infant mortality. Homozygous loss of the gene survival of motor neuron 1 (SMN1) causes the selective degeneration of lower motor neurons and subsequent atrophy of proximal skeletal muscles. The SMN1 protein product, survival of motor neuron (SMN), is ubiquitously expressed and is a key factor in the assembly of the core splicing machinery. The molecular mechanisms by which disruption of the broad functions of SMN leads to neurodegeneration remain unclear. We used an antisense oligonucleotide (ASO)-based inducible mouse model of SMA to investigate the SMN-specific transcriptome changes associated with neurodegeneration. We found evidence of widespread intron retention, particularly of minor U12 introns, in the spinal cord of mice 30 d after SMA induction, which was then rescued by a therapeutic ASO. Intron retention was concomitant with a strong induction of the p53 pathway and DNA damage response, manifesting as γ-H2A.X positivity in neurons of the spinal cord and brain. Widespread intron retention and markers of the DNA damage response were also observed with SMN depletion in human SH-SY5Y neuroblastoma cells and human induced pluripotent stem cell-derived motor neurons. We also found that retained introns, high in GC content, served as substrates for the formation of transcriptional R-loops. We propose that defects in intron removal in SMA promote DNA damage in part through the formation of RNA:DNA hybrid structures, leading to motor neuron death.

show abstract

Section: Significancementioning

confidence: 99%

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Jangi

Fleet

Cullen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

108

111

View full text Add to dashboard Cite

show abstract

“…Although a decrease of snRNP biogenesis has been observed in vitro [11], its connection to pathological changes in spinal motor neurons in SMA is not understood. Recent studies reveal that, besides being located in the nucleus, SMN protein also accumulates in the dendrites and axons of neurons and is associated with microtubules [12,13]. SMN protein can regulate β-actin, a major component of outgrowing axons [14].…”

Section: Introductionmentioning

confidence: 99%

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Wang

Zhang

2012

Cell Res

View full text Add to dashboard Cite

Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-∆7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

show abstract

“…However, SMN deficiency causes profound effects only on motoneurons but not on other cell types. SMN also exists in the axonal compartment of motoneurons where it is associated with heterogeneous nuclear RNP R and interacts with the 3 0 untranslated region of b-actin mRNA [11][12][13][14]. Reduced SMN results in lower levels of b-actin mRNA and protein in axons and growth cones.…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

et al. 2011

View full text Add to dashboard Cite

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive disorders in humans and is a common genetic cause of infant mortality. The disease is caused by loss of the survival of motoneuron (SMN) protein, resulting in the degeneration of alpha motoneurons in spinal cord and muscular atrophy in the limbs and trunk. One function of SMN involves RNA splicing. It is unclear why a deficiency in a housekeeping function such as RNA splicing causes profound effects only on motoneurons but not on other cell types. One difficulty in studying SMA is the scarcity of patient's samples. The discovery that somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) raises the intriguing possibility of modeling human diseases in vitro. We reported the establishment of five iPSC lines from the fibroblasts of a type 1 SMA patient. Neuronal cultures derived from these SMA iPSC lines exhibited a reduced capacity to form motoneurons and an abnormality in neurite outgrowth. Ectopic SMN expression in these iPSC lines restored normal motoneuron differentiation and rescued the phenotype of delayed neurite outgrowth. These results suggest that the observed abnormalities are indeed caused by SMN deficiency and not by iPSC clonal variability. Further characterization of the cellular and functional deficits in motoneurons derived from these iPSCs may accelerate the exploration of the underlying mechanisms of SMA pathogenesis.

show abstract

Active Transport of the Survival Motor Neuron Protein and the Role of Exon-7 in Cytoplasmic Localization

Cited by 250 publications

References 45 publications

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

SMN deficiency in severe models of spinal muscular atrophy causes widespread intron retention and DNA damage

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Brief Report: Phenotypic Rescue of Induced Pluripotent Stem Cell-Derived Motoneurons of a Spinal Muscular Atrophy Patient

Contact Info

Product

Resources

About