Lacomme M, Hales SC, Brown TW, Stevanovic K, Jolicoeur C, Cai J, Bois T, Desrosiers M, Dalkara D, Cayouette M. Numb regulates Tau levels and prevents neurodegeneration in tauopathy mouse models. Sci Adv. 2022 Oct 21;8(42):eabm4295. Epub 2022 Oct 19 PubMed.

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  1. This is truly a tour de force in terms of different methodologies and models they have used to conclude that Numb (especially 72 kDa isoform) interacts with tau, regulates intracellular tau levels, and provides neuroprotection in different model systems.

    The main takeaway from this study is that for the first time it implicates an important member of the Notch signaling pathway (which are typically involved in cell fate decision and cellular trafficking) as a novel regulator of intracellular pathological tau. It clearly demonstrates how enhancing Numb levels could bring down toxic tau levels inside the cell and it shows this is neuroprotective. They also nicely demonstrate that knocking down Numb does the opposite in retinal ganglion cells. This conclusion is based on solid sets of data both in vitro and in vivo model systems.

    There are lot of interesting aspects to this study, but to me, it was interesting to note that Numb (72) maintains intracellular tau homeostasis by secreting soluble (mostly monomeric) tau into the extracellular space to keep intracellular tau level well-balanced. This observation opens up more questions, including whether this extracellularly secreted tau acts as a “seed” for tau propagation (although the authors don’t seem to see any changes in the level of tau phosphorylation). This aspect needs further exploration. Nevertheless, this study identifies Numb as a novel regulatory to pathogenic tau and could serve as potential therapeutic target.

    View all comments by Kiran Bhaskar

  2. What distinguishes AD-associated tauopathy from other tauopathies is accelerated active tau secretion. This process does not occur via the conventional secretory pathway but is suggested to occur via “unconventional” endolysosomal secretion; namely upon the fusion of late-endosomal/multivesicular bodies with the cell surface.

    Besides supporting this mode of tau secretion in AD, this elegant study suggests how tau secretion might be linked to intraneuronal tau pathology and its neurotoxicity. Specifically, the authors interpret their findings to suggest that the endolysosomal pathway primarily secretes tau monomers, resulting in fewer intraneuronal tau oligomers, which are proposed to be more neurotoxic. 

    This interesting hypothesis seems to disagree with others that stipulate tau secretion itself might ultimately be neurotoxic. Future studies might disambiguate these hypotheses by blocking endolysosomal secretion and testing whether this worsens or ameliorates tau-related toxicity.

    View all comments by Scott Small

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