SMN and the Gemin proteins form sub-complexes that localise to both stationary and dynamic neurite granules

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

doi:10.1016/j.bbrc.2010.02.158

Cited by 21 publications

(23 citation statements)

References 31 publications

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“…We found that cell death after arsenite and H 2 O 2 treatment is inversely correlated with SMN expression levels and the number of SGs formed in these cells. Emetine, which disperses SGs in cells, eliminates the difference in sensitivity of P19-SMNi and P19-Con cells to treatment with sodium arsenite, strongly suggesting that the formation of SGs facilitated (Todd 2010)expression of SMN results in reduced formation of SGs in response to stresses, leading to cell death. Based on this hypothesis, we tested whether other proteins that promote assembly of SGs may compensate for the loss of SMN.…”

Section: Discussionmentioning

confidence: 93%

“…Aside from its roles in RNA processing, the SMN protein has also been implicated to function in axonal transport (Rossoll et al 2003;Zhang et al 2003;Carrel et al 2006) and forms granules in axons (Todd et al 2010). However, the fact that SMN protein is expressed in all tissues and provides a housekeeping function required by all cells cannot explain why low levels of SMN protein in the cells of SMA patients lead only to the specific loss of motor neurons.…”

Section: Introductionmentioning

confidence: 98%

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SMN Deficiency Reduces Cellular Ability to Form Stress Granules, Sensitizing Cells to Stress

et al. 2011

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Spinal Muscular Atrophy (SMA) is a neurodegenerative disease that is caused by deletion of the SMN (Survival of Motor Neuron) gene. The SMN protein is essential for cell survival and co-localized with TIA-1/R and G3BP, two characteristic markers of stress granules (SGs). To further study the SMN function in stress granules and in response to stress, we generated stable cell lines with SMN knockdown. Our data indicate that suppression of SMN drastically reduces cellular ability to form stress granules in response to stress treatment. In addition, we show that SMN deficiency sensitizes cells to sodium arsenite and H(2)O(2), two well-known stress inducers, leading to cell death at a much lower concentration of inducers in SMN knockdown cells than in control cells. Interestingly, the cell death is correlated with formation of stress granules, suggesting that involvement of SMN in formation of stress granules may play an important role in cell survival. Furthermore, rescue of SGs formation by overexpression of G3BP can reverse the defective formation of stress granules and results in partial abrogation of cell death against SMN deficiency. We deduce that modulation of stress response may be useful for potential SMN treatment.

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Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 98%

SMN Deficiency Reduces Cellular Ability to Form Stress Granules, Sensitizing Cells to Stress

et al. 2011

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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%

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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“…These granules also contain several known SMN-binding partners, including the Gemin proteins, Unrip, ZPR1 and profilin (Todd et al 2010b(Todd et al , 2010c. Theoretically, the reduced SMN protein levels in patients block/inhibit the active transport of specific mRNA subsets, resulting in the integral loss of protein regulation at the leading edges of neurones (Carrel et al 2006;Zhang et al 2003Zhang et al , 2006.…”

Section: Introductionmentioning

confidence: 97%

“…SMN is a component of the axonal transport granules that are involved in the transport of b-actin mRNA (Todd et al 2010a(Todd et al , 2010b(Todd et al , 2010cZhang et al 2003Zhang et al , 2006. These granules also contain several known SMN-binding partners, including the Gemin proteins, Unrip, ZPR1 and profilin (Todd et al 2010b(Todd et al , 2010c.…”

Section: Introductionmentioning

confidence: 98%

Mutations in the Survival Motor Neuron (SMN) Protein Alter the Dynamic Nature of Nuclear Bodies

et al. 2010

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The childhood disorder spinal muscular atrophy (SMA) is caused by reduced expression of the survival motor neuron (SMN) protein. SMN is a multifunctional protein that has been implicated in the production, processing and transport of RNA and ribonucleoproteins (RNPs). Within the nucleus, SMN is predominantly targeted to Cajal bodies (CB), which are involved in the maturation and processing of several subclasses of RNPs. Here, we show that the SMN exon 2b-encoded domain (SMN2b) is independently sufficient to mediate CB targeting, but that the resulting bodies are less dynamic than those containing full-length SMN protein. We also show that while two SMN proteins harbouring SMA-causing point mutations (A2G and S262I) are efficiently targeted to CBs, they also display reduced nuclear movement.

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SMN and the Gemin proteins form sub-complexes that localise to both stationary and dynamic neurite granules

Cited by 21 publications

References 31 publications

SMN Deficiency Reduces Cellular Ability to Form Stress Granules, Sensitizing Cells to Stress

SMN Deficiency Reduces Cellular Ability to Form Stress Granules, Sensitizing Cells to Stress

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

Mutations in the Survival Motor Neuron (SMN) Protein Alter the Dynamic Nature of Nuclear Bodies

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