Molecular mechanism of pT231-tau pathogenicity:

Tau protein abnormalities are associated with several neurodegenerative disorders, such as Alzheimer's disease (AD) and Traumatic brain injury (TBI). Axonal tau translocates into the nuclear compartment in tau-overexpressing SHSY5Y cells as well as Frontotemporal Dementia- Microtubule Associated Protein Tau (FTD-MAPT) Induced Pluripotent Stem Cell (iPS)-derived cortical neurons, resulting in neuronal dysfunction. Despite extensive consideration, it remains uncertain how tau translocation induces neurodegeneration. Here we employed starvation stress in primary cortical neurons and Single Severe TBI (ssTBI) in the cortices of male mouse brains as tauopathy models and studied the nuclear displacement of different P-tau species [Cis phosphorylated Thr231-tau (cis P-tau), Phosphorylated Ser202/Thr205-tau (AT8 P-tau), and Phosphorylated Thr212/Ser214-tau (AT100 P-tau)] at various time points. While all P-tau traveled into the somatodendritic compartment upon stress condition, cis P-tau translocated faster than the other species. Interestingly, P-tau nuclear localization coincided with p53 apoptotic stabilization as well as nucleolar stress, leading to neurodegeneration. Taken together, our findings reveal that P-tau nuclear translocation resulted in p53-dependent apoptosis and nucleolar dispersion, which in turn reflected neurodegeneration.

Schematic representation of P-tau nuclear translocation neurotoxicity

P53 is usually degraded with proteasomes, in which Mdm2 is the major factor. Under tauopathy stress conditions, pathogenic P-tau (cis P-tau, AT8, and AT100 P-tau) formed in the neurites. They gradually move from the neurites to the soma and nucleus. Mislocalized P-tau in the nucleus results in p53 stabilization, bax and active caspase-3 formation, and nucleolar dispersion, ultimately leading to neuron death. CisPt, Cis P-tau; AT8, AT8 P-tau; AT100, AT100 P-tau; CBax, Cleaved Bax; CCasp3, Cleaved Caspase-3; Cytoc, Cytochrome C.