Could a molecular traffic jam at the nuclear membrane explain one kind of motor neuron disease? Extensive hexanucleotide repeats in the C9ORF72 gene, which are transcribed into RNAs and translated into dipeptide oligomers, cause amyotrophic lateral sclerosis and frontotemporal dementia. Now, two papers published August 26 in Nature, and one in Nature Neuroscience, reveal that those repeats snarl traffic through pores in the nuclear envelope. “All three papers converge on the same cellular pathway,” said Fen-Biao Gao of the University of Massachusetts Medical School in Worcester, co-senior author on one of the Nature papers. “Nuclear-cytoplasmic transport is affected in C9 ALS-FTD.” However, the findings do not settle whether the repeat RNAs or the dipeptide repeats are responsible for the defect.

Fractured envelopes.

The nuclear envelope is normally smooth and round, but looks irregular in cells expressing C9ORF72 repeats. [Courtesy of Freibaum et al., 2015.]

“These three studies are remarkable for their convergence on nucleocytoplasmic transport,” commented Edward Lee of the University of Pennsylvania Perelman School of Medicine in Philadelphia, who was not involved in the work. “They clearly show that transport deficits are common to many experimental models of C9ORF72 toxicity, even those that are not based on artificial overexpression” (see full comment below).

All Arrows Point to the Nuclear Pores
C9ORF72’s hexanucleotide repeats—hundreds or thousands of them in some cases of ALS and FTD—are transcribed into repetitive RNAs, which are then translated into dipeptide repeats. Scientists believe either the RNA or peptides might be toxic to neurons (see Jan 2013 newsFeb 2013 news). The authors of each of the three new papers started with different assumptions about which does the dirty work. At Johns Hopkins University in Baltimore, Jeffrey Rothstein and colleagues focused on the RNAs. Aaron Gitler at Stanford University in Palo Alto, California, went after toxic effects of the dipeptides. Gao and co-senior author Paul Taylor of St. Jude Children’s Research Hospital in Memphis, Tennessee, studied fruit flies that make both, screening for genetic modifiers of repeat toxicity.

For the latter, co-first author Brian Freibaum at St. Jude expressed a construct containing 58 G4C2 repeats in Drosophila eyes. Flies have no C9ORF72 gene, and the construct included only the repeats, not the full gene. The result was a “rough eye” phenotype, in which the facets of the compound eye become disorganized.

Freibaum and co-first author Yubing Lu at UMass Medical School then crossed the hexanucleotide repeat model with fly deletion mutants, yielding four suppressors and 14 enhancers of the rough-eye phenotype. Because these 18 genes all were involved in nucleocytoplasmic shuttling, Lu examined the nuclei of fly cells expressing the repeats. He found the nuclear envelope to be in disarray, as judged by immunohistochemistry for the nuclear envelope protein Lamin C (see image above). “The nuclear membrane was frayed, like it was falling apart,” Taylor said. In addition, the protein Nup107, a component of nuclear pores, formed inclusions adjacent to the nuclear envelope. Something was clearly wrong with the gateway between nucleus and cytosol.

At the same time Freibaum and Lu were conducting these experiments, scientists led by co-senior authors Rothstein and Thomas Lloyd at Johns Hopkins were taking a different tack by examining the RNAs produced by the repeat. They also report their findings in Nature. Rothstein and colleagues had previously identified more than 400 human proteins that might bind C9ORF72 repeat RNA (see Oct 2013 news). They used that list to come up with candidate modifiers for their own screen, in this case using fruit flies that had abnormal eyes due to a 30-hexanucleotide repeat (Xu et al., 2013). From 385 of the repeat RNA-binding proteins that had orthologs in Drosophila, joint first authors Ke Zhang and Christopher Donnelley came up with 35 genetic modifiers of the rough-eye phenotype. Based on the prior RNA-binding study in human cells and the fly screen, one of the strongest hits was RanGAP1, activator of Ran GTPase, an enzyme that cycles between the nucleus and cytoplasm to direct traffic (Joseph, 2006). 

Co-author Aaron Haeusler, in the laboratory of Jiou Wang, confirmed by gel shift assay that RanGAP1 binds specifically to G4C2-repeat RNA. If overexpressed, RanGAP1 suppressed the repeat’s eye phenotype, while knocking down the activator worsened it.

Once the researchers were interested in nuclear transport, Zhang tested mutations in other nucleocytoplasmic transport proteins, such as RanGEF and importin-α. These genes, as well, affected repeat toxicity in flies. Mutations that enhanced nuclear import of proteins or blocked their export were beneficial, suggesting the C9ORF72 repeat prevents uptake of proteins into the nucleus. If this is the case, blocking export might help by keeping useful proteins inside the nucleus.

Meanwhile, the third research group, led by Gitler at Stanford, was also pursuing the effects of C9ORF72 repeats. Ana Jovičić, first author on the Nature Neuroscience paper, focused on the dipeptides that result from nonstandard translation of the hexanucleotide RNA. Because this occurs in all reading frames, five different dipeptides are created (two reading frames yield the same dipeptide). To distinguish the effects of repeat dipeptides from those of the repeat RNA, the authors constructed artificial genes that encoded an individual peptide without using the G4C2 sequence. Jovičić made constructs that generate 50-mers of each dipeptide, and expressed them in yeast. Because the most toxic ones were those containing arginine, Jovičić selected a proline-arginine-expressing yeast strain to screen for genes that would modify this toxicity. She identified 43 suppressors and 35 enhancers. When she grouped the modifiers by known function, nucleocytoplasmic transport emerged as the largest category, subsuming 11 genes.

What Does This Mean for ALS?
Because three separate screens pointed to nucleocytoplasmic transport as a central defect caused by G4C2 repeats in these disease models, the authors looked for direct evidence of faulty transport in human induced neurons made from the cells of C9ORF72 carriers and controls. Nucleocytoplasmic transport shepherds RNAs out of the nucleus, and proteins both in and out. The Gao/Taylor group focused on RNA trafficking, while the others probed protein shuttling.

Tracking fluorescently labeled RNA, Freibaum saw that neurons made from C9ORF72 carriers accumulated more RNA in the nucleus, and less in the cytoplasm, than control lines, suggesting a defect in RNA export.

To study protein trafficking, Gitler and colleagues stained cells for RCC1, a normally nuclear Ran guanine exchange factor and homolog of one of the enhancers of C9ORF72 toxicity identified in their yeast screen. While RCC1 inhabited the nucleus of induced neurons from controls, it was mostly cytoplasmic in induced neurons from expansion carriers. This suggests that nucleocytoplasmic protein transfer was altered in the human C9ORF72 lines, Jovičić concluded.

In Rothstein’s lab, co-first author Christopher Donnelly evaluated nuclear shuttling with a red fluorescent protein hooked to both a nuclear localization sequence and nuclear export signal so it would travel back and forth between the nucleus and the cytoplasm. He photobleached the reporter in induced neuron nuclei, then measured recovery of the fluorescence. It came back slowly in the C9ORF72 expansion neurons, indicating sluggish nuclear import.

Donnelly, who now runs his own lab at the University of Pittsburgh, further found that traffic of another ALS- and FTD-related protein, TDP-43, was perturbed in the human neurons. Cells derived from C9ORF72 mutation carriers tended to have more TDP-43 in the cytoplasm, and less in the nucleus. Donnelly suggested that defective nucleocytoplasmic transport might explain why other researchers have seen TDP-43 vacating the nucleus and aggregating in the cytoplasm in both C9ORF72-based disease and sporadic ALS (see Jan 2010 news). “We think that nuclear trafficking deficits might … promote [TDP-43] accumulation and TDP-43 pathology,” Donnelly said.

If nuclear trafficking was disrupted, the key players in that process, Ran and RANGAP1, might also be altered. Rothstein and colleagues confirmed this was the case. While RanGAP1 normally coats the nucleus of induced neurons smoothly, in the repeat-carrying cells it joined the RNA repeats in large, abnormal foci around the nucleus. This disrupted the localization of Ran, with less in the nucleus and more in the cytoplasm than normal. The authors found similar RANGAP1 defects in brain tissue from C9ORF72 expansion carriers who died of ALS. Other proteins of the nuclear pore complex also mislocalized in the ALS brain tissue. Based on these data, Rothstein said the C9ORF72 repeats cause two problems: disruption of transport by binding RanGAP1, and aggregation of nuclear pores. He said he does not know how those two defects are related.

Multiple Mechanisms?
Taylor noted that whether researchers figured the RNAs were toxic, or blamed the dipeptides, or went in without preconception as his group did, they all came to the same conclusion—that the repeats alter nucleocytoplasmic transport.

Even so, the scientists are still left wondering which repeat molecule—RNA or peptide—interferes with nucleocytoplasmic shuttling in human disease. Rothstein and Donnelly believe the RNA blocks the transport but could not rule out the possibility that dipeptides contributed in their models. Gitler and colleagues specifically expressed only dipeptide repeats in yeast, but do not know if those same peptides reach toxic levels in human neurons. Most scientists who spoke with Alzforum suggested that both RNAs and dipeptides might affect nucleocytoplasmic traffic.

None of the work offers any clues to C9ORF72’s normal function, since all groups studied just the repeats. However, in a recent study, researchers led by Janice Robertson of the University of Toronto reported that wild-type C9ORF72, without extra repeats, localizes to the nuclear envelope (see Aug 2015 news). It appeared to bind nuclear pore components there, though Robertson did not determine if C9ORF72 plays an active role in nucleocytoplasmic transport. Donnelly and Rothstein noted that they, too, detect full-length protein on the nuclear envelope. Researchers who spoke with Alzforum could not explain why the repeats and the normal protein seem to land in the same place, or if they perform similar functions once there. What they can conclude, Robertson said, is that nucleocytoplasmic transport clearly has a share in ALS pathology.

Could nucleocytoplasmic trafficking offer a new therapeutic target for FTD and ALS? Rothstein and colleagues gave their C9 repeat flies KPT-276, a small molecule that inhibits export from the nucleus. It rescued both transport deficit and eye phenotype. The authors surmised that blocking export with KPT-276 compensated for reduced import due to the repeats, normalizing protein levels inside and outside the nucleus. Donnelly plans to research related molecules further. Antisense oligonucleotides against the C9ORF72-repeat RNA also rescued both the fly-eye phenotype and the defective transport in induced neurons.

“These papers are an exciting advance for the field,” commented Adrian Isaacs of University College London, who did not participate in the work. “An important question is whether impaired nucleocytoplasmic transport plays a role in FTD and ALS without the C9ORF72 repeat expansion” (see full comment below). Rothstein told Alzforum his group will try to answer that.—Amber Dance


  1. These three studies are remarkable for their convergence on nucleocytoplasmic transport. Rarely does it happen that multiple groups, using multiple complementary approaches, from flies to yeast to neuronal cell culture models to human tissue, arrive at the same conclusion. There are still pressing questions—foremost, in my opinion, is why there is no correlation between dipeptide-repeat aggregates and neurodegeneration in human tissue. However, these studies clearly show that nucleocytoplasmic transport defects are common to many experimental models of C9ORF72 toxicity, even those that are not based on artificial overexpression. Finally, these studies add to the evidence that abnormal RNA pathways are a key feature of ALS and FTD, be it due to abnormal nucleocytoplasmic transport, nucleolar stress pathways, or dysregulation of TDP-43.

  2. These papers are an exciting advance for the field. An important question is whether impaired nucleocytoplasmic transport plays a role in FTD and ALS without C9ORF72 repeat expansion, particularly as the majority of FTD and ALS cases are characterized by mislocalization of nuclear TDP-43.

    The Gitler paper shows dipeptide repeats are sufficient to impair nucleocytoplasmic transport, so they would be my first bet for the culprit, but the repeat RNA-sequestering factors such as RanGAP could independently play a role. Both these possibilities require further investigation. For sequestration of RanGAP, soluble cytoplasmicrepeat RNA would most likely mediate the effect rather than RNA foci, which are generally nuclear and not in the appropriate location to sequester RanGAP, which is cytoplasmic.

  3. In a fascinating convergence, three papers have been published all implicating nucleocytoplasmic transport in the pathogenesis of disease associated with GGGGCC-repeat expansion of the C9ORF72 gene. This genetic variant has become extremely important in the field in recent years, as it is the most common genetic variant of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Indeed, it occurs in as many as 10 percent of all ALS patients and up to 40 percent of those with a positive family history of ALS and 25 percent of those with a positive family history of FTD (Majounie et al., 2012). Moreover, C9ORF72 disease resembles the more common sporadic form both clinically and pathologically, leading us to hope that therapies developed against C9ORF72 might be more broadly applicable (Cooper-Knock et al., 2012). Since the discovery of this genetic variant we have witnessed a number of step changes in our understanding: the discovery of RNA foci transcribed from the DNA repeat sequence in both a sense (DeJesus-Hernandez et al., 2011) and an antisense (Mizielinska et al., 2013) direction; then the discovery of dipeptide repeat proteins (DPR) translated from the repeat sequence (Mori et al., 2013). Both RNA foci and DPR proteins have been suggested as important mediators of toxicity in disease pathogenesis. The other prominent proposed pathogenic mechanism is haploinsufficiency. (Toxicity mechanisms are reviewed in Cooper-Knock et al., 2015). Now, again, we appear to have another step change in our understanding.

    A particularly interesting aspect of the focus on nucleocytoplasmic transport comes from properties of the nuclear pore complex highlighted by these studies. Nuclear pore proteins are long-lived, and the integrity of the nuclear pore complex is known to be affected by aging (D'Angelo et al., 2009); this fits well with an age-dependent disease caused by a genetic defect that is present from birth—perhaps aging exacerbates a phenotype present from early life, until a threshold is crossed that determines disease onset.

    The three papers take a related but certainly not identical approach. Broadly, they all focus on the identification of agents that ameliorate toxicity in a gain-of-function model of C9ORF72 disease, and show that these agents modulate genes and proteins involved in nucleocytoplasmic transport. However, there are important differences between the papers that deserve to be highlighted.

    Two of the papers (Freibaum et al. and Zhang et al.) focus on a drosophila model, whereas the third (Jovicic et al.) starts with a yeast model. Furthermore, two of the papers utilize an unbiased genetic screen for ameliorators and exaggerators of toxicity (Freibaum et al. and Jovicic et al.); analysis of these candidates showed they were enriched for proteins involved in nucleocytoplasmic transport. The other study analyzed candidates previously identified as binding partners of (and therefore potentially sequestered by) GGGCC-repeat RNA (Haeusler et al., 2014); overexpression of RanGAP, a protein involved in nucleocytoplasmic transport, was a potent suppressor of toxicity (Zhang et al.). None of the models is truly physiological in its reproduction of the human disease, although in each of the studies certain findings are validated in either human tissue or neurons derived from C9ORF72-patients. A note of caution should be sounded here—in the past year the field has witnessed a lot of excitement over the possible role of DPR proteins, particularly those which are arginine-rich (Mizielinska et al., 2014), only for other work to conclude that these species might be very rare and of uncertain significance in human tissue (Gomez-Deza et al., 2015). In addition, none of these models include expression of CCCCGG-repeat (antisense transcribed) RNA foci, and yet it has been suggested that the presence of these species is an important predictor of pathology in postmortem motor neurons from C9ORF72-ALS patients (Cooper-Knock et al., 2015).

    The yeast model utilized by Jovicic et al. is very different from the others in that it is a DPR-only model—the authors take care to express the DPR proteins in the absence of RNA foci. This is particularly important when one considers that the mechanism of toxicity suggested by Zhang et al. is based on sequestration of proteins by RNA foci—it seems counterintuitive to think that overexpression of a nucleocytoplasmic transport protein should still rescue toxicity when there are no RNA foci to sequester the protein and therefore initiate a relative loss of function. The complex interplay of factors raised by these studies remains to be resolved.

    Although all three papers agree that they are discovering an effect on nucleocytoplasmic transport, they raise quite different interpretations of the consequence of this effect. Freibaum et al. highlight an increase in the ratio of nuclear cytoplasmic RNA; they suggest the key to toxicity might be a compromise of nuclear export of RNA. In contrast, Zhang et al. suggest the key problem might be in transport of proteins carrying a nuclear import signal; notably, this includes TDP-43, whose mislocalization is perhaps the molecular hallmark of not only C9ORF72 disease, but of much of sporadic ALS and FTD.  Clearly nucleocytoplasmic transport has a broad set of functions in both RNA and protein transport and therefore a broad range of possible mechanisms need to be examined in the search for effective therapies. This is not the end, it is a new beginning.  


    . Clinico-pathological features in amyotrophic lateral sclerosis with expansions in C9ORF72. Brain. 2012 Mar;135(Pt 3):751-64. PubMed.

    . Antisense RNA foci in the motor neurons of C9ORF72-ALS patients are associated with TDP-43 proteinopathy. Acta Neuropathol. 2015 Jul;130(1):63-75. Epub 2015 May 6 PubMed.

    . The Spectrum of C9orf72-mediated Neurodegeneration and Amyotrophic Lateral Sclerosis. Neurotherapeutics. 2015 Apr;12(2):326-39. PubMed.

    . Age-dependent deterioration of nuclear pore complexes causes a loss of nuclear integrity in postmitotic cells. Cell. 2009 Jan 23;136(2):284-95. PubMed.

    . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20;72(2):245-56. Epub 2011 Sep 21 PubMed.

    . Dipeptide repeat protein inclusions are rare in the spinal cord and almost absent from motor neurons in C9ORF72 mutant amyotrophic lateral sclerosis and are unlikely to cause their degeneration. Acta Neuropathol Commun. 2015 Jun 25;3:38. PubMed.

    . C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature. 2014 Mar 13;507(7491):195-200. Epub 2014 Mar 5 PubMed.

    . Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study. Lancet Neurol. 2012 Apr;11(4):323-30. PubMed.

    . C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014 Sep 5;345(6201):1192-1194. Epub 2014 Aug 7 PubMed.

    . C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci. Acta Neuropathol. 2013 Oct 30; PubMed.

    . The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013 Mar 15;339(6125):1335-8. Epub 2013 Feb 7 PubMed.

  4. A perfect storm of research identifies nucleocytoplasmic shuttling defects as a tractable therapeutic target for ALS/FTD.

    Hexanucleotide repeat expansions (HRE) in C9ORF72 are the most common genetic cause of ALS/FTD (DeJesus-Hernandez et al., 2011; Renton et al., 2011). Three mechanisms of toxicity have been proposed:

    Understanding the mechanistic basis of this toxicity is vital to the development of effective therapies. Now, in a major advancement in the field, three independent teams have shown using genetic screens that toxicity caused by expression of C9ORF72 HREs in yeast and flies is due to defects in nucleocytoplasmic transport. Toxicity was dependent on repeat length, with longer repeats giving a more aggressive phenotype, as is observed in humans, although the absolute number of maximal repeats used in the studies was 58, which may not be pathologically significant in ALS/FTD7.

    In studies from the Gitler and Taylor teams, toxicity was clearly related to expression of arginine-rich DPR proteins through use of codon-optimized constructs, preventing expression of the GGGGCC repetitive sequence, thereby excluding the possibility of RNA-mediated toxicity. In contrast, the Rothstein team identified RanGAP1 as directly interacting with GGGGCC repeats in vitro, and confirmed the role of RanGAP1 in modifying C9ORF72-HRE toxicity in fly using a candidate genetic screen. Although the Rothstein team could not discount a contribution of DPRs in their model system, toxicity could be ameliorated by disruption of HRE G-quadruplexes, to which RanGAP1 binds, supporting an RNA-mediated mode of toxicity. Nevertheless, all three studies identified components of the nucleocytoplasmic transport machinery as suppressors/enhancers of toxicity caused by expression of C9ORF72 HREs.

    In another twist to the story, a recent publication from the Robertson group has shown that C9ORF72 is localized to the nuclear membrane of healthy motor neurons, but this is lost in diseased motor neurons in ALS, where C9ORF72 is mislocalized to the plasma membrane. Intriguingly, C9ORF72 was shown to interact with RanGTPase and Importin-β, again implicating defects of nucleocytoplasmic shuttling as a disease mechanism in ALS/FTD8.

    This perfect storm of findings clearly shows that defective nucleocytoplasmic transport has a key role in the disease mechanism causing ALS/FTD. The question remains as to what cargo, protein and/or RNA, either retained within or aberrantly exported from the nucleus, is responsible for toxicity. Is it a specific species, or multiple? In this regard, the Rothstein and Robertson teams showed that TDP-43 mislocalization from the nucleus to the cytoplasm correlated with defects of nucleocytoplasmic shuttling and/or loss of C9ORF72 from the nuclear membrane, respectively. This provides a direct link with the pathology pathognomonic of ALS/FTD.

    Whether mislocalization of TDP-43 is the major contributor to disease pathogenesis remains to be determined. However, restoring normal activity of nucleocytoplasmic shuttling is a tractable target for therapeutic intervention, and holds great promise as a treatment strategy for ALS/FTD.  


    . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011 Oct 20;72(2):245-56. Epub 2011 Sep 21 PubMed.

    . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011 Oct 20;72(2):257-68. Epub 2011 Sep 21 PubMed.

    . Unconventional translation of C9ORF72 GGGGCC expansion generates insoluble polypeptides specific to c9FTD/ALS. Neuron. 2013 Feb 20;77(4):639-46. PubMed.

    . 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. Lancet Neurol. 2012 Jan;11(1):54-65. PubMed.

    . The C9orf72 GGGGCC repeat is translated into aggregating dipeptide-repeat proteins in FTLD/ALS. Science. 2013 Mar 15;339(6125):1335-8. Epub 2013 Feb 7 PubMed.

    . RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia. Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E4968-77. Epub 2013 Nov 18 PubMed.

    . Jump from pre-mutation to pathologic expansion in C9orf72. Am J Hum Genet. 2015 Jun 4;96(6):962-70. Epub 2015 May 21 PubMed.

    . Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol. 2015 Oct;78(4):568-83. Epub 2015 Aug 29 PubMed.

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News Citations

  1. Chicago—RNA Inclusions Offer Therapeutic Target in ALS
  2. RNA Twist: C9ORF72 Intron Expansion Makes Aggregating Protein
  3. RNA Deposits Confer Toxicity in C9ORF72 ALS
  4. TDP-43: Modified and On the Move
  5. New C9ORF72 Antibodies Find Isoforms in Different Cellular Locations

Paper Citations

  1. . Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A. 2013 May 7;110(19):7778-83. PubMed.
  2. . Ran at a glance. J Cell Sci. 2006 Sep 1;119(Pt 17):3481-4. PubMed.

Further Reading


  1. . Nuclear contour irregularity and abnormal transporter protein distribution in anterior horn cells in amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2009 Nov;68(11):1184-92. PubMed.
  2. . Nuclear trafficking in health and disease. Curr Opin Cell Biol. 2014 Jun;28:28-35. Epub 2014 Feb 11 PubMed.
  3. . Regulation of mRNA trafficking by nuclear pore complexes. Genes (Basel). 2014 Sep 2;5(3):767-91. PubMed.
  4. . Regulation of nuclear import and export by the GTPase Ran. Int Rev Cytol. 2002;217:41-91. PubMed.
  5. . Extremely long-lived nuclear pore proteins in the rat brain. Science. 2012 Feb 24;335(6071):942. Epub 2012 Feb 2 PubMed.

Primary Papers

  1. . GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):129-33. Epub 2015 Aug 26 PubMed.
  2. . The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature. 2015 Sep 3;525(7567):56-61. Epub 2015 Aug 26 PubMed.
  3. . Modifiers of C9orf72 dipeptide repeat toxicity connect nucleocytoplasmic transport defects to FTD/ALS. Nat Neurosci. 2015 Sep;18(9):1226-9. PubMed.