Spontaneous Rupture and Entanglement of Human Neuronal Tau Protein Induced by Piconewton Compressive Force*

Mechanical force vector fluctuations in the living cells can have a significant impact on protein behavior and functions. We have observed abrupt and spontaneous tau protein ruptures under a compressive force ranging from ∼5 to ∼125 pN, at a biologically available force amplitude range in living cells, using a home-modified atomic force microscopy single-molecule manipulation. The rupture behavior is dependent on the physiological level of the presence of ions, such as K⁺ and Mg²⁺. We observed rupture events in the presence of K⁺ but not in the presence of Mg²⁺ ions. We have also explored the entangled protein state formed following the events of the multiple and simultaneous protein ruptures under crowding. Crowded proteins simultaneously rupture and then spontaneously refold to an entangled folding state, different from either folded or unfolded states of the tau protein, which can be a plausible pathway for the tau protein aggregation that is related to several neurodegenerative diseases, such as the Alzheimer’s and Parkinson’s Diseases.