title: Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy.
abstract: Frontotemporal lobar degeneration (FTLD) has been subdivided based on the main pathology found in the brains of affected individuals. When the primary pathology is aggregated, hyperphosphorylated tau, the pathological diagnosis is FTLD-tau. When the primary pathology is cytoplasmic and/or nuclear aggregates of phosphorylated TAR-DNA-binding protein (TDP-43), the pathological diagnosis is FTLD-TDP. Notably, TDP-43 pathology can also occur in conjunction with a number of neurodegenerative disorders; however, unknown environmental and genetic factors may regulate this TDP-43 pathology. Using transgenic mouse models of several diseases of the central nervous system, we explored whether a primary proteinopathy might secondarily drive TDP-43 proteinopathy. We found abnormal, cytoplasmic accumulation of phosphorylated TDP-43 specifically in two tau transgenic models, but TDP-43 pathology was absent in mouse models of Aβ deposition, α-synucleinopathy or Huntington's disease. Though tau pathology showed considerable overlap with cytoplasmic, phosphorylated TDP-43, tau pathology generally preceded TDP-43 pathology. Biochemical analysis confirmed the presence of TDP-43 abnormalities in the tau mice, which showed increased levels of high molecular weight, soluble TDP-43 and insoluble full-length and ~35 kD TDP-43. These data demonstrate that the neurodegenerative cascade associated with a primary tauopathy in tau transgenic mice can also promote TDP-43 abnormalities. These findings provide the first in vivo models to understand how TDP-43 pathology may arise as a secondary consequence of a primary proteinopathy.
authors.affiliation: Department of Neuroscience, Center for Translational Research in Neurodegenerative Disease, McKnight Brain Institute, University of Florida, 1275 Center Drive, BMS Building J-483, PO Box 100159, Gainesville, FL 32610-0244, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Clippinger
authors.forename: Simon
authors.initials: S
authors.lastname: D'Alton
authors.forename: Wen-Lang
authors.initials: WL
authors.lastname: Lin
authors.forename: Tania F
authors.initials: TF
authors.lastname: Gendron
authors.forename: John
authors.initials: J
authors.lastname: Howard
authors.forename: David R
authors.initials: DR
authors.lastname: Borchelt
authors.forename: Ashley
authors.initials: A
authors.lastname: Cannon
authors.forename: Yari
authors.initials: Y
authors.lastname: Carlomagno
authors.forename: Paramita
authors.initials: P
authors.lastname: Chakrabarty
authors.forename: Casey
authors.initials: C
authors.lastname: Cook
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.forename: Laura
authors.initials: L
authors.lastname: Ranum
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Schultheis
authors.forename: Guilian
authors.initials: G
authors.lastname: Xu
authors.forename: Leonard
authors.initials: L
authors.lastname: Petrucelli
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Benoit
authors.initials: B
authors.lastname: Giasson
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000473:pathology* / Q000648:ultrastructure; D010766:Phosphorylation / Q000235:genetics; D063146:Polycomb-Group Proteins; D053764:Presenilin-1 / Q000235:genetics; D024801:Tauopathies / Q000235:genetics / Q000473:pathology*; D014157:Transcription Factors / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D004268:DNA-Binding Proteins; C508853:PSEN1 protein, human; C533390:Phf1 protein, mouse; D063146:Polycomb-Group Proteins; D053764:Presenilin-1; D014157:Transcription Factors; D016875:tau Proteins