SMN, Gemin2 and Gemin3 Associate with β-Actin mRNA in the Cytoplasm of Neuronal Cells In Vitro

Todd, Adrian G.; Morse, Robert; Shaw, Debra J.; McGinley, Samuel; Stebbings, Howard; Young, Philip J.

doi:10.1016/j.jmb.2010.06.058

Cited by 32 publications

(36 citation statements)

References 38 publications

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“…As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10)(11)(12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described.…”

mentioning

confidence: 99%

Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

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

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Spinal muscular atrophy (SMA) is caused by depletion of the ubiquitously expressed survival motor neuron (SMN) protein, with 1 in 40 Caucasians being heterozygous for a disease allele. SMN is critical for the assembly of numerous ribonucleoprotein complexes, yet it is still unclear how reduced SMN levels affect motor neuron function. Here, we examined the impact of SMN depletion in Caenorhabditis elegans and found that decreased function of the SMN ortholog SMN-1 perturbed endocytic pathways at motor neuron synapses and in other tissues. Diminished SMN-1 levels caused defects in C. elegans neuromuscular function, and smn-1 genetic interactions were consistent with an endocytic defect. Changes were observed in synaptic endocytic proteins when SMN-1 levels decreased. At the ultrastructural level, defects were observed in endosomal compartments, including significantly fewer docked synaptic vesicles. Finally, endocytosis-dependent infection by JC polyomavirus (JCPyV) was reduced in human cells with decreased SMN levels. Collectively, these results demonstrate for the first time, to our knowledge, that SMN depletion causes defects in endosomal trafficking that impair synaptic function, even in the absence of motor neuron cell death.endocytic trafficking | survival motor neuron | spinal muscular atrophy | C. elegans | infection S pinal muscular atrophy (SMA) is one of the most severe neuromuscular diseases of childhood, with an incidence of 1 in 10,000 live births and a high carrier frequency of roughly 1 in 40 Caucasians (1-3). SMA is caused by reduced levels of the ubiquitously expressed survival of motor neuron (SMN) protein and results in degeneration of α-spinal cord motor neurons, muscle weakness, and/or death. Two human genes encode the SMN protein, SMN1 and SMN2. SMA alleles arise at relatively high frequency due to small intrachromosomal de novo rearrangements including the SMN1 locus (4). Patients often carry homozygous SMN1 deletions, although missense and nonsense alleles exist (5). Multiple copies of SMN2 rarely compensate for loss of SMN1 due to a C > T nucleotide change in SMN2 exon 7 that perturbs pre-mRNA splicing and results in a truncated protein of diminished function and stability (SMNΔ7) (5-9).SMN has numerous roles and interacts with various proteins, yet it remains unclear which interactions are most pertinent to SMA pathogenesis. As a component of the Gemin complex, SMN is required for biogenesis of small nuclear ribonucleoprotein (snRNP) particles critical for pre-mRNA splicing (10-12). Furthermore, SMN is needed for stress granule formation (13,14), is found in RNP granules moving through neuronal processes, and is part of RNP complexes implicated in synaptic local translation (15)(16)(17)(18)(19)(20). Additional roles for SMN, in transcription (21), in the PTEN-mediated protein synthesis pathway (22), in translational control (23), and in cell proliferation/differentiation (24), have been described. Importantly, no consensus has been reached regarding the cellular and molecular pathways wh...

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mentioning

confidence: 99%

Decreased function of survival motor neuron protein impairs endocytic pathways

Dimitriadi

Derdowski

Kalloo

et al. 2016

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

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“…This nuclear localization pattern suggests a role for SMN in nuclear snRNP maturation and regeneration. In neurons, SMN forms cytoplasmic granules in neurites and www.intechopen.com growth cones and participates in active bidirectional transport of mRNAs (Fallini, et al, 2011;Todd, et al, 2010;H. Zhang, et al, 2006).…”

Section: Smn and Its Cellular Localizationmentioning

confidence: 99%

Recent Advances in Understanding of Alternative Splicing in Neuronal Pathogenesis

Chen¹,

Lin²,

Tarn³

2011

RNA Processing

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“…Indeed, SMN has been localized within actively transported granules in neurites of cultured motor neurons, where it associates specifically with Gemin proteins but not the Sm proteins [29,[87][88][89]. This suggests that the role of these transport ribonucleoprotein granules is independent of snRNP assembly.…”

Section: B-actin Mrna Axonal Transportmentioning

confidence: 99%

“…This interaction is required for correct b-actin mRNA translocation along the axon to the growth cone and thus essential for neuronal outgrowth and presynaptic differentiation [76,91]. Recently, the analysis of the SHSY5Y neuroblastoma cell line showed the colocalization of b-actin and cytoplasmic SMNcontaining granules [89], thus supporting a role for SMN in b-actin mRNA transport. In fact, SMN-depleted motor neurons display reduced localization of both hnRNP and b-actin along the axons and at the growth cones [76].…”

Section: B-actin Mrna Axonal Transportmentioning

confidence: 99%

The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis

2010

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Spinal muscular atrophy (SMA) is the leading genetic cause of infant death, affecting 1 in 6000-10,000 live births. SMA is an autosomal recessive disorder characterized by the degeneration of a-motor neurons, and lower limb and proximal muscle weakness and wasting. SMA is the result of the deletion of or mutations in the survival motor neuron (SMN)1 gene. Currently, our understanding of how loss of the widely expressed SMN leads to the selective pathogenesis observed in SMA is limited. Here, we discuss the known nuclear and cytoplasmic functions of the SMN protein and how they relate to the SMA pathology reported in motor neurons, striated muscle and at neuromuscular junctions. While a vast amount of work in various cell and animal models has increased our knowledge of the many functions of the SMN protein, we have yet to come to a full understanding of which role(s) are central to SMA pathogenesis.Keywords n actin dynamics n neurodegeneration n preclinical models n snRNP assembly n spinal muscular atrophy n survival motor neuron ReviewFor reprint orders, please contact: reprints@futuremedicine.com

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SMN, Gemin2 and Gemin3 Associate with β-Actin mRNA in the Cytoplasm of Neuronal Cells In Vitro

Cited by 32 publications

References 38 publications

Decreased function of survival motor neuron protein impairs endocytic pathways

Decreased function of survival motor neuron protein impairs endocytic pathways

Recent Advances in Understanding of Alternative Splicing in Neuronal Pathogenesis

The many faces of SMN: deciphering the function critical to spinal muscular atrophy pathogenesis

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