Figure 5

Schematic model of nuclear trafficking of cyclin T1 and it alterations by PGRN and GRN. Cyclin T1 binds PGRN and some of its GRN derivatives when co-expressed in COS7 cells [91]. A) When cyclin T1 is expressed with full length PGRN, both proteins are localized in the cytoplasm. B) In contrast, when expressed with the C-terminal GRN, CDE, cyclin T1 and GRN are found in the nucleus, enabling down-stream transcription elongation. Given the evidence that PGRN and GRN are associated with translocation of proteins such as cyclin T1 from cytoplasm to nucleus, it is tempting to hypothesize that PGRN might be involved in similar regulation of TDP-43 nuclear-cytoplasmic translocation. With decreased functional PGRN in FTLD-U associated with PGRN mutations, TDP-43 translocation might be perturbed, leading to accumulation in the cytoplasm and formation of NCI.