Science raises two main points: the nature of the trafficking is changing, and US support for programs targeting trafficking in Russia is wavering. Between and no seizures of fissile material were reported to the IAEA. Since , there have been six cases of plutonium and HEU trafficking. Two of these cases had not previously been reported in open-source documents: a report on 2 October of 1.
For the other cases cited by Science, see abstracts , , , In addition, Science mentions a plan by workers in a weapons lab to divert For this case, see abstracts , , Science reports that while pre trafficking of Russian nuclear materials was into Eastern Europe, trafficking in the post wave has involved Central Asia, the Caucasus, and Turkey. Science suggests that the post cases cast doubt on the effectiveness of increased security on Russia's borders after , and that the southern route indicates that countries such as Iran, Afghanistan, Pakistan, Syria, and Iraq could be destinations of contraband nuclear material.
Science argues that two US programs aimed at combatting nuclear materials trafficking are receiving insufficient government support. The Bush administration's FY budget request for the U.
While, under physiological conditions, phosphorylation may serve in fine tuning the nuclear-cytoplasmic shuttling of FET proteins, increased or decreased phosphorylation of C-terminal tyrosine residue could lead to their cytoplasmic mislocalization and aggregation. Recent papers have connected molecular events arising from the C9orf72 mutation with perturbation of the nuclear transport and a downstream effect on TDP mislocalization. This will be covered in detail in the section on C9ORF TDP is translocated into the nucleus by the classical import pathway.
Replacement of the basic residues in NLS with alanine or serine promotes cytoplasmic localization and aggregation of TDP in primary neurons Ayala et al. TDP is also found condensed in intranuclear inclusions, mainly in familial FTLD with VCP mutations, suggesting that a perturbation of nuclear export might also play some role in the disease Neumann et al. Indeed, TDP carries a leucine-rich nuclear export signal located between amino acids and , which enables its export from the nucleus to the cytoplasm Winton et al.
Replacement of the hydrophobic residues in the nuclear export signal with alanine, prevents TDP from exiting the nucleus and leads to the formation of intranuclear inclusions Winton et al. Several studies have shown that TDP levels have an impact on the nuclear transport, suggesting a potential feed-back regulation mechanism Ward et al. Overall, the regulation of the nuclear transport machinery by TDP raises a question as to whether initial modest TDP mislocalization and aggregation can impair nuclear transport on its own and form a positive feedback loop, causing more TDP to accumulate and aggregate in the cytoplasm.
Transcription of the antisense strand has also been observed, as well as formation of antisense RNA foci Donnelly et al. Inclusions of TDP aggregates in brain and spinal cord are prevalent in the majority of patients carrying the repeat expansion, with some brain regions less commonly affected with the pathology Al-Sarraj et al. Recent studies show that all three hypothesized disease mechanisms, namely C9ORF72 haploinsufficiency, RNA toxicity, and DPR toxicity, may, either independently or concurrently, affect the nuclear transport process, also resulting in TDP mislocalization and aggregation.
Some of the C9orf72 HRE mutation-bearing RNA is transported to the cytoplasm, where it either accumulates and sequesters proteins involved in nucleocytoplasmic trafficking 8 , or it is translated into DPR proteins 9. In turn, some of the DPR proteins aggregate and sequester nucleocytoplasmic transport related proteins For details see Fig 1. Proteins with reduced levels and potential modifiers of toxicity are in dashed outline.
In two studies on different Drosophila models, a possible role for the sense repeat RNAs in the disturbances of nucleocytoplasmic trafficking has been identified Table 1 Freibaum et al. As a consequence, the RAN gradient is disturbed, resulting in impaired translocation of RNA and proteins through the nuclear pore complex. Importantly, G 4 C 2 expression also led to cytoplasmic accumulation of TDP in salivary gland cells of Drosophila and in C9orf72 patient iPSC-derived neurons, suggesting impaired nuclear import as the root pathomechanism Zhang et al.
Consistently, in a second Drosophila study, a dominant-negative form of RAN strongly enhanced the neurodegeneration in flies expressing G 4 C 2 Freibaum et al. Cells transiently expressing expanded G 4 C 2 repeats, as well as iPSC derived cortical neurons from patients with the C9orf72 -related disease, show nuclear retention of their mRNAs Freibaum et al.
This suggests a disease mechanism of toxic over-accumulation of mRNA in the nucleus due to reduction of clearance resulting from either deficient RAN independent mRNA export or deficient degradation.
However, neither of the two initial Drosophila studies was set up to differentiate between RNA and DPR toxicity as the cause of the nuclear transport perturbation. Six of them belong to the karyopherin family and their upregulation rescued the toxicity but did not impact DPR localization or levels. As in yeast, DPR toxicity was linked to the perturbation of the protein equilibrium of nuclear pore complex proteins, importins, exportins, and regulators of the RAN-GTP cycle in Drosophila model Boeynaems et al.
The authors suggest a mechanism whereby PR repeats bind to TNPO1, thus replacing its cargoes and causing their mislocalization. Most recently, GA aggregates have been shown to sequester proteins involved in nucleocytoplasmic transport Zhang et al.
Much more work is needed to decipher the involvement of different groups of modifiers of nucleocytoplasmic shuttling i. Over time proteins in these droplets start to aggregate and give rise to insoluble fibrillar structures. As these liquid droplets have stress granule-like properties, a stress granule origin of insoluble aggregates is further substantiated.
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Nuclear trafficking in amyotrophic lateral sclerosis and frontotemporal lobar degeneration Sonja Prpar Mihevc. Oxford Academic. Google Scholar. Simona Darovic. Anja Kovanda. Boris Rogelj. Correspondence to: Assoc. Cite Citation. Permissions Icon Permissions.
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Abstract Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are two ends of a phenotypic spectrum of disabling, relentlessly progressive and ultimately fatal diseases. In the cytoplasm, import-associated KPNBs bind the NLS on the cargo or cargo complex and then translocate across the nuclear pore complex into the nucleus. Figure 1. Open in new tab Download slide. As the severity of nuclear import block and cytoplasmic mislocalization of individual mutations correlates with the age of disease onset and its progression, nuclear import impairment appears to be a key event in the mechanism of ALS-FUS Bosco et al.
An additional requirement may be an age-related increase in cell stress. Several forms of cell stress have been shown to lead to formation of FUS-positive stress granules, which are believed to be precursors of insoluble aggregates in the cytoplasm. Prolonged cell stress may cause growth and coalescence of the granules, giving rise to cytoplasmic inclusions Bosco et al. Figure 2. Figure 3.
Using specific antibodies against the long C9-L and short C9-S forms of C9ORF72, the latter was found at the nuclear membrane in healthy control spinal motor neurons, although, in ALS patients HRE mutation positive and negative , it was localized to the plasma membrane Fig. Figure 4. Table 1. Cytoplasmic hGle1A regulates stress granules by modulation of translation. Search ADS. An amyotrophic lateral sclerosis-linked mutation in GLE1 alters the cellular pool of human Gle1 functional isoforms.
Structural determinants of the cellular localization and shuttling of TDP FUS mutations in amyotrophic lateral sclerosis: clinical, pathological, neurophysiological and genetic analysis. Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules.
Multiple roles of TDP in gene expression, splicing regulation, and human disease. Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Phosphorylation of C-terminal tyrosine in FUS impairs its nuclear import. Nuclear carrier and RNA-binding proteins in frontotemporal lobar degeneration associated with fused in sarcoma FUS pathological changes.
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C9ORF72, implicated in amytrophic lateral sclerosis and frontotemporal dementia, regulates endosomal trafficking. Fifty years of nuclear pores and nucleocytoplasmic transport studies: multiple tools revealing complex rules. CRM1 is responsible for intracellular transport mediated by the nuclear export signal. A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study.
Proteomic analysis of methylarginine-containing proteins in HeLa cells by two-dimensional gel electrophoresis and immunoblotting with a methylarginine-specific antibody. Binding site distribution of nuclear transport receptors and transport complexes in single nuclear pore complexes.
Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis.
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