bims-nucpor 2021-10-24 papers

Issue of 2021–10–24
four papers selected by
Sara Mingu, Johannes Gutenberg University

Front Cell Neurosci. 2021 ;15 742763

Mislocalization of Nucleocytoplasmic Transport Proteins in Human Huntington's Disease PSC-Derived Striatal Neurons.

Jenny Lange, Alison Wood-Kaczmar, Aneesa Ali, Sahar Farag, Rhia Ghosh, Jennifer Parker, Caroline Casey, Yumiko Uno, Akiyoshi Kunugi, Patrizia Ferretti, Ralph Andre, Sarah J Tabrizi.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene (HTT). Disease progression is characterized by the loss of vulnerable neuronal populations within the striatum. A consistent phenotype across HD models is disruption of nucleocytoplasmic transport and nuclear pore complex (NPC) function. Here we demonstrate that high content imaging is a suitable method for detecting mislocalization of lamin-B1, RAN and RANGAP1 in striatal neuronal cultures thus allowing a robust, unbiased, highly powered approach to assay nuclear pore deficits. Furthermore, nuclear pore deficits extended to the selectively vulnerable DARPP32 + subpopulation neurons, but not to astrocytes. Striatal neuron cultures are further affected by changes in gene and protein expression of RAN, RANGAP1 and lamin-B1. Lowering total HTT using HTT-targeted anti-sense oligonucleotides partially restored gene expression, as well as subtly reducing mislocalization of proteins involved in nucleocytoplasmic transport. This suggests that mislocalization of RAN, RANGAP1 and lamin-B1 cannot be normalized by simply reducing expression of CAG-expanded HTT in the absence of healthy HTT protein.

Keywords: Huntington’s disease; antisense oligonucleotide; nuclear pore complex; pluripotent stem cell (PSC); striatal neurons

DOI: https://doi.org/10.3389/fncel.2021.742763

Adv Sci (Weinh). 2021 Oct 17. e2102757

Impact of the Nuclear Envelope on Malignant Transformation, Motility, and Survival of Lung Cancer Cells.

Sílvio Terra Stefanello, Isabelle Luchtefeld, Ivan Liashkovich, Zoltan Pethö, Ihab Azzam, Etmar Bulk, Gonzalo Rosso, Lilly Döhlinger, Bettina Hesse, Andrea Oeckinghaus, Victor Shahin.

Nuclear pore complexes (NPCs) selectively mediate all nucleocytoplasmic transport and engage in fundamental cell-physiological processes. It is hypothesized that NPCs are critical for malignant transformation and survival of lung cancer cells, and test the hypothesis in lowly and highly metastatic non-small human lung cancer cells (NSCLCs). It is shown that malignant transformation is paralleled by an increased NPCs density, and a balanced pathological weakening of the physiological stringency of the NPC barrier. Pharmacological interference using barrier-breaking compounds collapses the stringency. Concomitantly, it induces drastic overall structural changes of NSCLCs, terminating their migration. Moreover, the degree of malignancy is found to be paralleled by substantially decreased lamin A/C levels. The latter provides crucial structural and mechanical stability to the nucleus, and interacts with NPCs, cytoskeleton, and nucleoskeleton for cell maintenance, survival, and motility. The recent study reveals the physiological importance of the NPC barrier stringency for mechanical and structural resilience of normal cell nuclei. Hence, reduced lamin A/C levels in conjunction with controlled pathological weakening of the NPC barrier stringency may facilitate deformability of NSCLCs during the metastasis steps. Modulation of the NPC barrier presents a potential strategy for suppressing the malignant phenotype or enhancing the effectiveness of currently existing chemotherapeutics.

Keywords: cancer; cellular physiology and biophysics; nanomedicine; nuclear envelope; nuclear pores

DOI: https://doi.org/10.1002/advs.202102757

BMC Biol. 2021 Oct 20. 19(1): 226

Channel nuclear pore protein 54 directs sexual differentiation and neuronal wiring of female reproductive behaviors in Drosophila.

Mohanakarthik P Nallasivan, Irmgard U Haussmann, Alberto Civetta, Matthias Soller.

BACKGROUND: Female reproductive behaviors and physiology change profoundly after mating. The control of pregnancy-associated changes in physiology and behaviors are largely hard-wired into the brain to guarantee reproductive success, yet the gene expression programs that direct neuronal differentiation and circuit wiring at the end of the sex determination pathway in response to mating are largely unknown. In Drosophila, the post-mating response induced by male-derived sex-peptide in females is a well-established model to elucidate how complex innate behaviors are hard-wired into the brain. Here, we use a genetic approach to further characterize the molecular and cellular architecture of the sex-peptide response in Drosophila females.
RESULTS: Screening for mutations that affect the sensitivity to sex-peptide, we identified the channel nuclear pore protein Nup54 gene as an essential component for mediating the sex-peptide response, with viable mutant alleles leading to the inability of laying eggs and reducing receptivity upon sex-peptide exposure. Nup54 directs correct wiring of eight adult brain neurons that express pickpocket and are required for egg-laying, while additional channel Nups also mediate sexual differentiation. Consistent with links of Nups to speciation, the Nup54 promoter is a hot spot for rapid evolution and promoter variants alter nucleo-cytoplasmic shuttling.
CONCLUSIONS: These results implicate nuclear pore functionality to neuronal wiring underlying the sex-peptide response and sexual differentiation as a response to sexual conflict arising from male-derived sex-peptide to direct the female post-mating response.

Keywords: Neuronal wiring; Nuclear pore complex (NPC); Nup54; Post-mating behaviors; Sexual differentiation; pickpocket (ppk) neurons

DOI: https://doi.org/10.1186/s12915-021-01154-6

Transplant Proc. 2021 Oct 18. pii: S0041-1345(21)00642-4. [Epub ahead of print]

Alterations in the Nucleocytoplasmic Transport in Heart Transplant Rejection.

Silvia Lozano-Edo, Ignacio Sánchez-Lázaro, Luis Almenar-Bonet, Manuel Portolés, Maryem Ezzitouny, Estefanía Tarazón, Esther Roselló-Lleti, Raquel Lopez-Vilella, Luis Martínez-Dolz.

BACKGROUND: Nucleocytoplasmic transport is a crucial process for cell function. Previous studies have observed alterations in different molecules involved in it, relating them to ventricular function. However, there are no published data evaluating possible differences in the expression of these molecules in heart transplantation (HT) recipients. Our objective is to evaluate whether its levels are related to the appearance of cellular rejection (CR) during the first year after HT.
METHODS: A prospective clinical cohort that included patients undergoing HT between January 2017 and January 2019 (n = 46). Blood samples for the analysis of importin 5 (IMP5), nucleoporin 153 (Nup153); RAN-GTPaseAP1 (RanGAP1), and sarcoplasmic reticulum calcium ATPase (ATP-aseCaTransp) were collected approximately 2 months post-HT. The levels obtained were correlated with the incidence of at least moderate CR during the first year of follow-up.
RESULTS: Results showed that 17.39% of the patients had at least moderate CR during the first year of follow-up. Higher levels of IMP5, Nup153, and RanGAP1 were observed in this group. This difference was statistically significant in the case of Nup153 and RanGAP1 (15.94 ± 14.00 vs 28.62 ± 23.61, P = .048; 21.95 ± 15.97 vs 40.90 ± 27.16, P = .026, respectively); there was an opposite trend in the ATP-aseCaTransp case.
CONCLUSION: Patients with at least a moderate degree of CR during follow-up showed higher serum levels of IMP5, Nup153, and RanGAP1. The prognostic usefulness of the determination of these biomarkers and whether their elevation during follow-up would facilitate early, noninvasive identification of patients with CR remains to be clarified.

DOI: https://doi.org/10.1016/j.transproceed.2021.09.003