A Missing Origin of the Tau Protein Aggregation Pathway Triggered by Thermal and Biological Forces

Fluctuations in mechanical force vectors within living cells can substantially influence the behavior and functions of proteins. Tau protein can spontaneously be raptured and entangled in refolding under picoNewton compressive forces that are biologically available in a living cell: a hidden aggregation pathway due to stress and crowding. Our findings were achieved through a customized modification of atomic force microscopy (AFM) for single-molecule manipulation. This previously hidden phenomenon of proteins rupturing collectively while subsequently and spontaneously refolding into a complex entangled conformation, distinct from the Tau protein’s folded or unfolded states, could potentially explain the early-event initiation of the aggregation of the Tau protein seen in various neurodegenerative diseases. This article introduces our recent discovery of the missing Tau protein property that is of significant relevance to the Tau protein and neurodegenerative disease research and medical treatment, aiming to stimulate the collective observation and a new perspective on the Tau aggregation mechanism and disease mechanism studies.

Keywords

Tau protein

aggregation

mechanical force

neuronal degenerate diseases

Funding

Ohio Eminent Scholar Endowment

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Fig. 1.

Single-molecule compressive force analysis of Tau proteins. (A) The force curve presented here depicts the characteristic pattern observed during the rupture of a Tau protein under a compressive force. The sudden decrease in the force curve corresponds to the spontaneous rupture of the protein molecule. To validate these spontaneous protein-tertiary structure rupture events, we conducted a series of systematic control experiments [15, 27, 28]. (B) The cartoon scheme below illustrates the process of Tau protein rupture under a compressive force: (i) At the initial stage, there is no physical contact between the atomic force microscopy (AFM) tip and the protein molecule. (ii) As the contact is established, the molecule becomes squeezed under the applied compressive force. The black arrows in the scheme represent the force vectors acting on the molecule, the AFM tip, and the cover glass. (iii) As the compressive force increases, it eventually reaches a threshold value. Simultaneously, the molecular interaction weakens to a point where it can no longer withstand the force. Consequently, the protein molecule undergoes rupture. (iv) The final state depicted in the scheme represents the spontaneously ruptured state of the protein. Please note that this is a simplified cartoon scheme illustrating the concept and not an exact representation of the molecular structure or the forces involved. (C) The distribution of threshold rupture force was plotted against the rupture force loading distance using a force loading rate of 3000 pN/s. This analysis aimed to examine the relationship between the applied force and the corresponding threshold force required for rupture. (D) A typical compressive force curve on a Tau protein under an Mg ${}^{2+}$ (2 mM) environment demonstrates the response of the protein to applied compressive forces. Adapted with permission from [15]. Copyright 2019 American Chemical Society.

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J. Integr. Neurosci. Print ISSN 0219-6352 Electronic ISSN 1757-448X