Hyperphosphorylation-Induced Phase Transition in Vesicle Delivery Dynamics of Motor Proteins in Neuronal Cells
arxiv(2024)
摘要
Synaptic vesicle transport by motor proteins along microtubules is a crucial
active process underlying neuronal communication. It is known that microtubules
are destabilized by tau-hyperphosphorylation, which causes tau proteins to
detach from microtubules and form neurofibril tangles. However, how
tau-phosphorylation affects transport dynamics of motor proteins on the
microtubule remains unknown. Here, we discover that long-distance
unidirectional motion of vesicle-motor protein multiplexes (VMPMs) in living
cells is suppressed under tau-hyperphosphorylation, with the consequent loss of
fast vesicle-transport along the microtubule. The VMPMs in hyperphosphorylated
cells exhibit seemingly bidirectional random motion, with dynamic properties
far different from VMPM motion in normal cells. We establish a parsimonious
physicochemical model of VMPM's active motion that provides a unified,
quantitative explanation and predictions for our experimental results. Our
analysis reveals that, under hyperphosphorylation conditions,
motor-protein-multiplexes have both static and dynamic motility fluctuations.
The loss of the fast vesicle-transport along the microtubule can be a mechanism
of neurodegenerative disorders associated with tau-hyperphosphorylation.
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