title: Frontotemporal dementia-associated N279K tau mutant disrupts subcellular vesicle trafficking and induces cellular stress in iPSC-derived neural stem cells.
abstract: BACKGROUND
  Pallido-ponto-nigral degeneration (PPND), a major subtype of frontotemporal dementia with parkinsonism related to chromosome 17 (FTDP-17), is a progressive and terminal neurodegenerative disease caused by c.837 T > G mutation in the MAPT gene encoding microtubule-associated protein tau (rs63750756; N279K). This MAPT mutation induces alternative splicing of exon 10, resulting in a modification of microtubule-binding region of tau. Although mutations in the MAPT gene have been linked to multiple tauopathies including Alzheimer's disease, frontotemporal dementia and progressive supranuclear palsy, knowledge regarding how tau N279K mutation causes PPND/FTDP-17 is limited.
  
  
  RESULTS
  We investigated the underlying disease mechanism associated with the N279K tau mutation using PPND/FTDP-17 patient-derived induced pluripotent stem cells (iPSCs) and autopsy brains. In iPSC-derived neural stem cells (NSCs), the N279K tau mutation induced an increased ratio of 4-repeat to 3-repeat tau and accumulation of stress granules indicating elevated cellular stress. More significant, NSCs derived from patients with the N279K tau mutation displayed impaired endocytic trafficking as evidenced by accumulation of endosomes and exosomes, and a reduction of lysosomes. Since there were no significant differences in cellular stress and distribution of subcellular organelles between control and N279K skin fibroblasts, N279K-related vesicle trafficking defects are likely specific to the neuronal lineage. Consistently, the levels of intracellular/luminal vesicle and exosome marker flotillin-1 were significantly increased in frontal and temporal cortices of PPND/FTDP-17 patients with the N279K tau mutation, events that were not seen in the occipital cortex which is the most spared cortical region in the patients.
  
  
  CONCLUSIONS
  Together, our results demonstrate that alterations of intracellular vesicle trafficking in NSCs/neurons likely contribute to neurodegeneration as an important disease mechanism underlying the N279K tau mutation in PPND/FTDP-17.
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. melissachloewren@gmail.com.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Wren
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Zhao.Jing@mayo.edu.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Liu.chiachen@mayo.edu.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Murray.Melissa@mayo.edu.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Murray
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Atagi.Yuka@mayo.edu.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Atagi
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Davis.Mary2@mayo.edu.
authors.forename: Mary D
authors.initials: MD
authors.lastname: Davis
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. fuyuan2011@yahoo.com.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Division of Regenerative Medicine, Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo, 105-8461, Japan. hjokano@jikei.ac.jp.
authors.forename: Hirotaka J
authors.initials: HJ
authors.lastname: Okano
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. koogaki@juntendo.ac.jp.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Ogaki
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. strongosky.audrey2@mayo.edu.
authors.forename: Audrey J
authors.initials: AJ
authors.lastname: Strongosky
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Tacik.Pawel@mayo.edu.
authors.forename: Pawel
authors.initials: P
authors.lastname: Tacik
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Rademakers.Rosa@mayo.edu.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rademakers
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Ross.Owen@mayo.edu.
authors.forename: Owen A
authors.initials: OA
authors.lastname: Ross
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Dickson.Dennis@mayo.edu.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.affiliation: Department of Neurology, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Wszolek.Zbigniew@mayo.edu.
authors.forename: Zbigniew K
authors.initials: ZK
authors.lastname: Wszolek
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. Kanekiyo.takahisa@mayo.edu.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kanekiyo
authors.affiliation: Department of Neuroscience, Mayo Clinic Jacksonville, 4500 San Pablo Road, Jacksonville, FL, 32224, USA. bu.guojun@mayo.edu.
authors.forename: Guojun
authors.initials: G
authors.lastname: Bu
mesh_terms: D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D058732:Embryoid Bodies; D011992:Endosomes / Q000502:physiology; D005091:Exons / Q000235:genetics; D055354:Exosomes / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000378:metabolism / Q000473:pathology; D057180:Frontotemporal Dementia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D008247:Lysosomes / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009778:Occipital Lobe / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D021381:Protein Transport; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013702:Temporal Lobe / Q000378:metabolism / Q000473:pathology; D022161:Transport Vesicles / Q000502:physiology*; D016875:tau Proteins / Q000235:genetics*
chemical_list: C054369:MAPT protein, human; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C106354:flotillins; D016875:tau Proteins