Mislocalization of NPC components has been reported in several neurodegenerative diseases, including TDP-43 proteinopathies and Alzheimer’s disease.  As the NPC is the conduit for nucleocytoplasmic transport, abnormalities in the NPC may lead to nucleocytoplasmic transport defects.  The localization of NPC components has not previously been examined in primary tauopathies, such as frontotemporal lobar degeneration-tau (FTLD-tau), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD).

Sections from frontal and occipital cortices from five cases each of neurologically normal controls, FTLD-tau, PSP, and CBD were obtained from the Massachusetts Alzheimer’s Disease Research Center.  Midbrain sections for five cases each of control, PSP, and CBD were also obtained.  Multiplex immunofluorescence was used to stain the sections for NPC component nucleoporin 98 (Nup98), phospho-tau (AT8 antibody), and neuronal soma marker MAP2.  Slides were visualized on an Olympus VS120 Virtual Slide Microscope.

In frontal cortex, control and PSP cases showed a generally uniform nuclear localization of Nup98, but FTLD-tau and CBD cases showed a more heterogenous nuclear localization of Nup98 and a mislocalization of Nup98 to the cytoplasm in AT8-positive neurons.  In occipital cortex, Nup98 had a generally uniform nuclear localization in control and primary tauopathy sections, except for some FTLD-tau cases that showed cytoplasmic mislocalization in AT8-positive neurons.  In midbrain, control tissue had a generally uniform nuclear localization of Nup98, whereas AT8-positive neurons in PSP and CBD cases had a cytoplasmic mislocalization of Nup98.

Disruption of the normal nuclear staining pattern and/or cytoplasmic mislocalization of NPC component Nup98 was seen in AT8-positive neurons in several primary tauopathies, suggesting alterations in the NPC are a common feature of a wide range of neurodegenerative diseases.  Further understanding of the functional implications of NPC disruption may give insights into the pathophysiology of primary tauopathies.