Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration

Abstract

Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT-III pathway emerges as a critical player in the surveillance and preservation of well-assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT-III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear-cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.

Keywords: ALS; ESCRT; FTD; neurodegeneration; nuclear pore complex; nucleocytoplasmic transport; nucleoporins.

Figure 1:. Nuclear pore complex, nuclear envelope, and nuclear transport receptor pathology in neurodegeneration.

Graphical depiction of Nup, NTR, and nuclear envelope pathologies documented in neurodegenerative disease. Normally, intact and functional NPCs maintain proper nucleocytoplasmic compartmentalization. NTRs (red circles) facilitate the active nucleocytoplasmic trafficking of macromolecules between the nucleus and cytoplasm. The ESCRT-III protein CHMP7 (purple circles) can passively diffuse into the nucleus to maintain NPC and nuclear envelope homeostasis (in cooperation with other ESCRT-III proteins). However, nuclear levels remain low due to active nuclear export. TDP-43 (green circles) is predominantly localized to the nucleus where it functions to regulate transcription and splicing of its mRNA targets. TDP-43 is also involved in mRNA transport and translation, though its cytoplasmic localization is typically minimal. In ALS the abnormal nuclear accumulation of CHMP7 is sufficient to initiate a reduction of Nups from the NPC leading to their subsequent degradation via the proteasome and lysosome. This collective reduction of multiple Nups from the neuronal NPC impacts functional nucleocytoplasmic transport (dashed arrows) which in turn, at least in part, contributes to nuclear loss of TDP-43 function and localization. Loss of nuclear TDP-43 localization and function impacts expression and splicing of target RNAs potentially contributing to loss of function for their associated proteins. We note that the majority of studies to date have been largely descriptive and thus, the molecular mechanisms that give rise to Nup, NPC, NTR, and nuclear envelope alterations in disease remain largely unknown. Nonetheless, defects in nucleocytoplasmic transport (dashed arrows), nuclear mRNA accumulation (presumably through impaired RNA export), and cytoplasmic Nup, NTR, and protein aggregation have been documented in models of ALS, FTD, and HD. Additionally, in Tau-based FTD models, nuclear envelope invaginations and perinuclear Nup – Tau co-aggregations have been observed. In HD, intranuclear accumulations comprised of mutant Htt protein and Nups or NTRs have been reported. Figure created with BioRender.