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Padmanabhan P, Kneynsberg A, Cruz E, Amor R, Sibarita JB, Götz J. Single-molecule imaging reveals Tau trapping at nanometer-sized dynamic hot spots near the plasma membrane that persists after microtubule perturbation and cholesterol depletion. EMBO J. 2022 Oct 4;41(19):e111265. Epub 2022 Aug 25 PubMed.
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University of Cambridge
These are very interesting observations revealing the presence of transient tau accumulations that form at, or very near, the plasma membrane. It remains to be determined whether these structures result from tau’s ability to interact with lipids, or arise via protein-protein interaction (or some combination of both).
As the authors note, the results instantly raise a lot of questions as to the functional relevance of these structures. What is the relationship between the hotspots and fibrillar tau aggregation? Could these local densities promote the conversion of tau from native soluble protein to filamentous aggregates? And is there a link between these tau assemblies and the unconventional secretion of tau?
An understanding of the molecular requirements for formation of the hotspots could be very revealing, and a good place to start for future studies. Investigating the requirements in tau might provide important information to the role of the structures. For instance, if known modifiers of tau secretion, such as mutation of its cysteine residues (Katsinelos et al., 2021), were to impact hotspot formation, it would suggest that the two phenomena are linked. Determining whether the hotspots are observed with protein-free lipid vesicles would help determine the nature of the interaction.
Finally, determining whether the hotspot structures are present in neural tissue is important to understand their relevance to the physiological condition. The paper adds a new dimension to our understanding of tau’s distribution in the cell and demonstrates the power of super-resolution techniques in revealing new biology.
References:
Katsinelos T, McEwan WA, Jahn TR, Nickel W. Identification of cis-acting determinants mediating the unconventional secretion of tau. Sci Rep. 2021 Jun 21;11(1):12946. PubMed.
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