Fig. 1

Representation of the nucleus and NPCs with Nups, protein/RNA aggregates in several neurodegenerative diseases. ALS/FTD: - Damaged NPC and specific Nups involved in the presence of TDP-43 cytoplasmic aggregates and impaired TDP-43 nuclear import. - Impaired FUS import in the presence of aggregates containing FUS with the importin TNPO1 or alone. - Impaired RNA export in C9ORF72 mutations with DPRs and TDP-43 protein aggregates formation. - Altered Ran and RCC1 nucleo-cytoplasmic distribution; C9ORF72 toxicity is increased by GLE1. - EXOSC3 dysfunction. - Altered distribution of importin-α and -β in SOD1 mutation with Nup62 impairment. HD: HTT physiological transport across the NPC through the interaction of NES with TPR and XPO1. Aberrant shuttling of RAN proteins and MAP2 due to PolyQ HTT affecting the NPC. Intranuclear aggregates of PolyQ HTT sequestering Nup62, Nup88, GLE1, and RanGAP1. AD: Phospho-tau aggregates induce NPC damage and accumulation of NTF2 and Nup98 in the cytoplasm; Nup98 loss, in turn, may facilitate tau aggregation. PD: Cytoplasmic aggregates and intranuclear alpha-synuclein in Parkinson’s disease; pCREB aggregates and nuclear accumulation of NFkB are associated with NPC and Nup358 defects in PD