TFEB and V-ATPase-mediated Lysosomal Stress Sensing Pathway in Tauopathy


Early work revealed that TFEB is highly effective in ameliorating tau/NFT pathology and rescuing cognitive impairment and neurodegeneration. TFEB targets only the aberrant tau species and this specificity may be conferred by a unique tau-induced V-ATPase-mediated TFEB stress sensing and signaling program. This project is to determine TFEB PTM signatures induced by tau that drive TFEB nuclear signaling.

The hypothesis is that intraneuronal Tau accumulation acts as a lysosomal stress signal to activate TFEB and V-ATPase expression. Further, effective TFEB/V-ATPase signaling is critical for lysosomal homeostasis and immune regulation in the context of Tau/NFT pathology. This will be testing using novel mouse models and cutting-edge technologies collectively developed by the PO1 investigators.

Project Aims

  • Identify Tau-induced TFEB post-translational modifications and proteoforms.
  • Determine Tau-induced lysosomal proteome and metabolome changes and test TFEB dependency,
  • Decipher the role of TFEB/B-ATPase signaling in lysosome-immune relationship.


Martini-Stoica, H., Cole, A.L., Swartzlander, D.B., Chen, F., Wan, Y.-W., Bajaj, L., Bader, D.A., Lee, V.M.-Y., Trojankowski, J.Q., Liu, Z., Sardiello, M., and Zheng, H. TFEB enhances astroglial uptake of extracellular tau species and reduces tau spreading. J. Exp. Med. 2018; 215(9): 2355-77. PMCID: PMC6122971.

Xu, Y., Zhang, S., and Zheng, H. The cargo receptor SQSTM1 ameliorates neurofibrillary tangle pathology and spreading through selective targeting of pathological MAPT (microtubule associated protein Tau). Autophagy 2019; 15(4): 583-98. PMCID: PMC6526869.

Xu, Y., Du, S., Marsh, J.A., Horie, K., Sato, C., Ballabio, A., Karch, C.M., Holtzman, D.M., and Zheng, H. TFEB regulates lysosomal exocytosis of tau and its loss of function exacerbates tau pathology and spreading. Mol. Psych. 2020; PMCID: PMC7609570.

Xu, Y., Propson, N.E., Du, S., Xiong, W., and Zheng, H. Autophagy deficiency modulates microglial lipid homeostasis and aggravates tau pathology and spreading. Proc. Natl. Acad. Sci. USA 2021; 118(27): e2023418118.