Page 40 - Q. Neuroscience

[Q. Neuroscience-23]

XPn interacts with microtubules to impair the function of tau

for neurite degeneration

Hyejin Park¹˙#, Youngwon Kim¹˙#, Yong-Keun Jung¹˙*

¹School of Biological Science, Seoul National University, seoul 08826, korea

X proteins (XPs) play a key role in nucleotide metabolism via nucleotide phosphoryl exchange. A new member of

this family, XPn, has recently been identified, but its function remains largely unknown. In this study, we report that

neuronal XPn mediates amyloid-beta (Aβ) or ROS-mediated neurite degeneration and neurotoxicity. We find that
XPn is mainly expressed in the hippocampus and cortex of the mouse brains. Compared to XK1, purified XPn protein
shows little kinase activity in vitro. From pull-down and LC/MS/MS analysis, we isolated tubulins as an interaction

partner of XPn in the mouse brains. XPn expression is significantly up-regulated in the neuronal cells upon exposure
to Aβ and hydrogen peroxides (H2O2), and ectopic expression of XPn augments neurite degeneration and neuronal

death. Accordingly, XPn knockdown neuronal cells are resistant to Aβ or H2O2-induced neurite degeneration and
cell death. Interestingly, XPn antagonizes the interaction of microtubules and tau in vitro and in neuronal cells. Thus,

we conclude that XPn plays a novel detrimental role in Aβ or ROS-mediated neurite degeneration via its interaction
with microtubules to modulate the function of tau, providing insight into a mechanism for tau-mediated

neurodegeneration in AD.