TY - JOUR
T1 - Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy
AU - Clippinger, Amy K.
AU - D'Alton, Simon
AU - Lin, Wen Lang
AU - Gendron, Tania F.
AU - Howard, John
AU - Borchelt, David R.
AU - Cannon, Ashley
AU - Carlomagno, Yari
AU - Chakrabarty, Paramita
AU - Cook, Casey
AU - Golde, Todd E.
AU - Levites, Yona
AU - Ranum, Laura
AU - Schultheis, Patrick J.
AU - Xu, Guilian
AU - Petrucelli, Leonard
AU - Sahara, Naruhiko
AU - Dickson, Dennis W.
AU - Giasson, Benoit
AU - Lewis, Jada
N1 - Funding Information:
Acknowledgments We would like to acknowledge funding from the “The Pick’s Disease Excellence in Research Fund from Mrs. Warren Henderson” to JL, Santa Fe HealthCare Alzheimer's Disease Research Center to DRB and GX, University of Florida to DRB, TEG, LR, NS, BG, and JL, and Mayo Clinic to LP and DWD.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - Mouse
KW - Neuropathology, tauopathy
KW - TDP-43
KW - TDP-43 proteinopathies
KW - Tau
KW - Transgenic
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U2 - 10.1007/s00401-013-1123-8
DO - 10.1007/s00401-013-1123-8
M3 - Article
C2 - 23666556
AN - SCOPUS:84879564918
SN - 0001-6322
VL - 126
SP - 39
EP - 50
JO - Acta neuropathologica
JF - Acta neuropathologica
IS - 1
ER -