PMID- 32295833
OWN - NLM
STAT- MEDLINE
DCOM- 20210603
LR  - 20240229
IS  - 1535-9484 (Electronic)
IS  - 1535-9476 (Print)
IS  - 1535-9476 (Linking)
VI  - 19
IP  - 6
DP  - 2020 Jun
TI  - Dysregulation of Exosome Cargo by Mutant Tau Expressed in Human-induced 
      Pluripotent Stem Cell (iPSC) Neurons Revealed by Proteomics Analyses.
PG  - 1017-1034
LID - S1535-9476(20)34995-1 [pii]
LID - 10.1074/mcp.RA120.002079 [doi]
AB  - 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.
CI  - (c) 2020 Podvin et al.
FAU - Podvin, Sonia
AU  - Podvin S
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 
      San Diego, La Jolla, California.
FAU - Jones, Alexander
AU  - Jones A
AD  - Biomedical Sciences Graduate Program, University of California, San Diego, La 
      Jolla, California.
FAU - Liu, Qing
AU  - Liu Q
AD  - Department of Neurosciences, School of Medicine, University of California San 
      Diego, La Jolla, California.
FAU - Aulston, Brent
AU  - Aulston B
AD  - Department of Neurosciences, School of Medicine, University of California San 
      Diego, La Jolla, California.
FAU - Ransom, Linnea
AU  - Ransom L
AD  - Biomedical Sciences Graduate Program, University of California, San Diego, La 
      Jolla, California.
FAU - Ames, Janneca
AU  - Ames J
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 
      San Diego, La Jolla, California.
FAU - Shen, Gloria
AU  - Shen G
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 
      San Diego, La Jolla, California.
FAU - Lietz, Christopher B
AU  - Lietz CB
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 
      San Diego, La Jolla, California.
FAU - Jiang, Zhenze
AU  - Jiang Z
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 
      San Diego, La Jolla, California.
FAU - O'Donoghue, Anthony J
AU  - O'Donoghue AJ
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 
      San Diego, La Jolla, California.
FAU - Winston, Charisse
AU  - Winston C
AD  - Department of Neurosciences, School of Medicine, University of California San 
      Diego, La Jolla, California.
FAU - Ikezu, Tsuneya
AU  - Ikezu T
AD  - Department of Pharmacology and Experimental Therapeutics, Department of 
      Neurology, Alzheimer's Disease Research Center, Boston University, School of 
      Medicine, Boston, Massachusetts.
FAU - Rissman, Robert A
AU  - Rissman RA
AD  - Department of Neurosciences, School of Medicine, University of California San 
      Diego, La Jolla, California; VA San Diego Healthcare System, La Jolla, 
      California.
FAU - Yuan, Shauna
AU  - Yuan S
AD  - Department of Neurosciences, School of Medicine, University of California San 
      Diego, La Jolla, California.
FAU - Hook, Vivian
AU  - Hook V
AD  - Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, 
      San Diego, La Jolla, California; Department of Neurosciences, School of Medicine, 
      University of California San Diego, La Jolla, California. Electronic address: 
      vhook@ucsd.edu.
LA  - eng
GR  - RF1 AG054199/AG/NIA NIH HHS/United States
GR  - T32 GM007752/GM/NIGMS NIH HHS/United States
GR  - I01 BX004312/BX/BLRD VA/United States
GR  - R01 AG054672/AG/NIA NIH HHS/United States
GR  - R56 AG057469/AG/NIA NIH HHS/United States
GR  - T32 MH019934/MH/NIMH NIH HHS/United States
GR  - R01 NS094597/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20200415
PL  - United States
TA  - Mol Cell Proteomics
JT  - Molecular & cellular proteomics : MCP
JID - 101125647
RN  - 0 (ANP32A protein, human)
RN  - 0 (MAPT protein, human)
RN  - 0 (Nuclear Proteins)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (tau Proteins)
RN  - EC 3.1.3.16 (Protein Phosphatase 2)
SB  - IM
MH  - Alzheimer Disease/genetics/*metabolism
MH  - Animals
MH  - Brain/metabolism/pathology
MH  - Cells, Cultured
MH  - Chromatography, Liquid
MH  - Computational Biology
MH  - Exosomes/*metabolism/pathology
MH  - Gene Ontology
MH  - Humans
MH  - Induced Pluripotent Stem Cells/metabolism
MH  - Mutation
MH  - Neurons/*metabolism/pathology
MH  - Nuclear Proteins/metabolism
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Interaction Maps
MH  - Protein Phosphatase 2/antagonists & inhibitors/metabolism
MH  - *Proteomics
MH  - RNA-Binding Proteins/metabolism
MH  - Tandem Mass Spectrometry
MH  - tau Proteins/genetics/*metabolism
PMC - PMC7261814
OTO - NOTNLM
OT  - Exosomes
OT  - alzheimer's disease
OT  - biogenesis
OT  - dysregulation
OT  - human
OT  - iPSC neurons
OT  - mutant tau
OT  - networks
OT  - neurobiology
OT  - neurodegenerative diseases
OT  - protein identification
OT  - signaling molecules
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2020/04/17 06:00
MHDA- 2021/06/04 06:00
PMCR- 2020/04/15
CRDT- 2020/04/17 06:00
PHST- 2020/04/07 00:00 [received]
PHST- 2020/04/17 06:00 [pubmed]
PHST- 2021/06/04 06:00 [medline]
PHST- 2020/04/17 06:00 [entrez]
PHST- 2020/04/15 00:00 [pmc-release]
AID - S1535-9476(20)34995-1 [pii]
AID - RA120.002079 [pii]
AID - 10.1074/mcp.RA120.002079 [doi]
PST - ppublish
SO  - Mol Cell Proteomics. 2020 Jun;19(6):1017-1034. doi: 10.1074/mcp.RA120.002079. 
      Epub 2020 Apr 15.