Abstract
Accumulation and propagation of hyperphosphorylated Tau (p-Tau) is a common neuropathological hallmark associated with neurodegeneration of Alzheimer’s disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), and related tauopathies. Extracellular vesicles, specifically exosomes, have recently been demonstrated to participate in mediating Tau propagation in brain. Exosomes produced by human induced pluripotent stem cell (iPSC)-derived neurons expressing mutant Tau (mTau), containing the P301L and V337M Tau mutations of FTDP-17, possess the ability to propagate p-Tau pathology after injection into mouse brain. To gain an understanding of the mTau exosome cargo involved in Tau pathogenesis, these pathogenic exosomes were analyzed by proteomics and bioinformatics. The data showed that mTau expression dysregulates the exosome proteome to result in 1) proteins uniquely present only in mTau, and not control exosomes, 2) the absence of proteins in mTau exosomes, uniquely present in control exosomes, and 3) shared proteins which were significantly upregulated or downregulated in mTau compared with control exosomes. Notably, mTau exosomes (not control exosomes) contain ANP32A (also known as I1PP2A), an endogenous inhibitor of the PP2A phosphatase which regulates the phosphorylation state of p-Tau. Several of the mTau exosome-specific proteins have been shown to participate in AD mechanisms involving lysosomes, inflammation, secretases, and related processes. Furthermore, the mTau exosomes lacked a substantial portion of proteins present in control exosomes involved in pathways of localization, vesicle transport, and protein binding functions. The shared proteins present in both mTau and control exosomes represented exosome functions of vesicle-mediated transport, exocytosis, and secretion processes. These data illustrate mTau as a dynamic regulator of the biogenesis of exosomes to result in acquisition, deletion, and up- or downregulation of protein cargo to result in pathogenic mTau exosomes capable of in vivo propagation of p-Tau neuropathology in mouse brain.
Original language | English (US) |
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Pages (from-to) | 1017-1034 |
Number of pages | 18 |
Journal | Molecular and Cellular Proteomics |
Volume | 19 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2020 |
Bibliographical note
Funding Information:* This research was supported by NIH grant R56 AG057469 (awarded to T.I., R.R., and V.H.), NIH R01 NS094597 (awarded to V.H.), and ITN start-up funds to S.Y. A. Jones was supported by NIH T32GM007752 (awarded to J.H. Brown), and C.L. was supported by NIH T32MH019934 (awarded to D. Jeste). The authors declare that they have no conflicts of interest with the contents of this article. □S This article contains supplemental Figures and Tables. ‡‡ To whom correspondence should be addressed: Dr. Vivian Hook, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Dr. MC0657, La Jolla, CA 92093-0657. Tel.: 858-822-6682; E-mail: [email protected].
Publisher Copyright:
© 2020 Podvin et al. Published by The American Society for Biochemistry and Molecular Biology, Inc.