The disruption of nucleocytoplasmic transport (NCT) is an important mechanism in neurodegenerative diseases. In the case of C9orf72-ALS, trafficking of macromolecules through the nuclear pore complex (NPC) might get frustrated by the binding of C9orf72-translated arginine-containing dipeptide repeat proteins (R-DPRs) to the Kapβ family of nuclear transport receptors. Besides Kapβs, several other types of transport components have been linked to NCT impairments in R-DPR-expressed cells, but the molecular origin of these observations has not been clarified. Here, we adopt a coarse-grained molecular dynamics model at amino acid resolution to study the direct interaction between polyPR, the most toxic DPR, and various nuclear transport components to elucidate the binding mechanisms and provide a complete picture of potential polyPR-mediated NCT defects. We found polyPR to directly bind to several isoforms of the Impα family, CAS (the specific exporter of Impα) and RanGAP. We observe no binding between polyPR and Ran. Longer polyPRs at lower salt concentrations also make contact with RanGEF and NTF2. Analyzing the polyPR contact sites on the transport components reveals that polyPR potentially interferes with RanGTP/RanGDP binding, with nuclear localization signal (NLS)-containing cargoes (cargo-NLS) binding to Impα, with cargo-NLS release from Impα, and with Impα export from the nucleus. The abundance of polyPR-binding sites on multiple transport components combined with the inherent polyPR length dependence makes direct polyPR interference of NCT a potential mechanistic pathway of C9orf72 toxicity.

As an ailment, leishmaniasis is still an incessant challenge in neglected tropical diseases and neglected infections of poverty worldwide. At present, the diagnosis and treatment to combat Leishmania tropical infections are not substantial remedies and require advanced & specific research. Therefore, there is a need for a potential novel target to overcome established medicament modalities\' limitations in pathogenicity. In this review, we proposed a few ab initio findings in nucleoporins of nuclear pore complex in Leishmania sp. concerning other infectious protists. So, through structural analysis and dynamics studies, we hypothesize the nuclear pore molecular machinery & functionality. The gatekeepers Nups, export of mRNA, mitotic spindle formation are salient features in cellular mechanics and this is regulated by dynamic nucleoporins. Here, diverse studies suggest that Nup93/NIC96, Nup155/Nup144, Mlp1/Mlp2/Tpr of Leishmania Species can be a picked out marker for diagnostic, immune-modulation, and novel drug targets. In silico prediction of nucleoporin-functional interactors such as NUP54/57, RNA helicase, Ubiquitin-protein ligase, Exportin 1, putative T-lymphocyte triggering factor, and 9 uncharacterized proteins suggest few more noble targets. The novel drug targeting to importins/exportins of Leishmania sp. and defining mechanism of Leptomycin-B, SINE compounds, Curcumins, Selinexor can be an arc-light in therapeutics. The essence of the review in Leishmania\'s nucleoporins is to refocus our research on noble molecular targets for tropical therapeutics.
UNASSIGNED: The online version contains supplementary material available at 10.1007/s12639-022-01515-0.