Jiang L, Chakraborty P, Zhang L, Wong M, Hill SE, Webber CJ, Libera J, Blair LJ, Wolozin B, Zweckstetter M. Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress. Sci Adv. 2023 Feb 3;9(5):eadd9789. Epub 2023 Feb 1 PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. This is a solid paper in terms of biochemistry/biophysics. The authors document an interaction between tau and FKBP in vitro, and specify the interaction mode. It is possible that the FKBP is binding and regulating tau in cells, but the co-localization experiments are not conclusive. I would have liked to see, e.g., an immunoprecipitation showing a direct interaction in cells. One thing the authors could have done would be to modify amino acids in tau that change binding to FKBP and then test if that alters the rescue effects of FKBP. FKBP binds a lot of substrates, as they note, thus many of the protective effects they assert could easily be indirect, and not related to binding to tau.

    View all comments by Marc Diamond

  2. It is well known in the field that by inhibiting tau-mediated pathologies and synaptic dysfunction, FK506 is protective in neurodegenerative diseases, including frontotemporal dementia (Yoshiyama et al., 2007), Alzheimer’s disease (Miller et al., 2014) and Parkinson’s disease (Teravskis et al., 2018). FKBP12 is one of the best-characterized receptors of FK506, which was initially developed as an immunosuppressive drug but was found to be a strong inhibitor of long-term depression (LTD), a form of synaptic plasticity, as well as a rescuer of pathological forms of LTD. How, was unclear. The reported direct interaction between FKBP12 and tau will help solve this decade-long puzzle in the field.

    The authors reported that FKBP12 binds to a unique structural motif of tau and that its overexpression protects against tau pathologies and prevents neurodegeneration in a tauopathy model. This significantly advances the field by providing a novel mechanism by which FK506 inhibits tau pathologies and tau-mediated pathophysiology. Moreover, tau mislocalization from axons to postsynaptic structures including the somatodendritic domain is believed to be a common mechanism underlying the pathobiology of multiple neurodegenerative disease. The upstream signaling cascade that causes this tau mislocalization remains elusive. The reported oligomeric tau-induced co-mislocalization of FKBP12 and tau to the somatodendritic domain may also shed new light upon this unresolved puzzle. Nevertheless, although highly novel, this interaction between tau and FKBP12 provides limited information for how tau, FKBP12, and calcineurin mediate tau pathophysiology in neurodegenerative diseases. Further studies are needed to determine whether FKBP12 acts upstream to or downstream from tau and calcineurin.

    References:

    Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.

    Miller EC, Teravskis PJ, Dummer BW, Zhao X, Huganir RL, Liao D. Tau phosphorylation and tau mislocalization mediate soluble Aβ oligomer-induced AMPA glutamate receptor signaling deficits. Eur J Neurosci. 2014 Apr;39(7):1214-24. PubMed.

    Teravskis PJ, Covelo A, Miller EC, Singh B, Martell-Martínez HA, Benneyworth MA, Gallardo C, Oxnard BR, Araque A, Lee MK, Liao D. A53T Mutant Alpha-Synuclein Induces Tau-Dependent Postsynaptic Impairment Independently of Neurodegenerative Changes. J Neurosci. 2018 Nov 7;38(45):9754-9767. Epub 2018 Sep 24 PubMed.

    View all comments by Dezhi Liao

Make a Comment

To make a comment you must login or register.

This paper appears in the following:

News

  1. The Chaperone FKBP12 Shields Tau from Aggregation