Back to Search
Start Over
Robust cytoplasmic accumulation of phosphorylated TDP-43 in transgenic models of tauopathy
- Source :
- Acta Neuropathologica
- Publisher :
- Springer Nature
-
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. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1123-8) contains supplementary material, which is available to authorized users.
- Subjects :
- Genetically modified mouse
Cytoplasm
Pathology
medicine.medical_specialty
Mouse
TDP-43
Transgene
Central nervous system
Clinical Neurology
Polycomb-Group Proteins
Mice, Transgenic
tau Proteins
Biology
medicine.disease_cause
Transgenic
Presenilin
Pathology and Forensic Medicine
Amyloid beta-Protein Precursor
Mice
Cellular and Molecular Neuroscience
mental disorders
Presenilin-1
medicine
Animals
Humans
Phosphorylation
Microscopy, Immunoelectron
Neurons
TDP-43 proteinopathies
Regulation of gene expression
Original Paper
Mutation
Brain
nutritional and metabolic diseases
Frontotemporal lobar degeneration
medicine.disease
nervous system diseases
DNA-Binding Proteins
Disease Models, Animal
medicine.anatomical_structure
Gene Expression Regulation
Tauopathies
Neurology (clinical)
Tauopathy
Tau
Neuropathology, tauopathy
Transcription Factors
Subjects
Details
- Language :
- English
- ISSN :
- 00016322
- Volume :
- 126
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Acta Neuropathologica
- Accession number :
- edsair.doi.dedup.....1f572d55c8bc89c4281adc7a8ec11d31
- Full Text :
- https://doi.org/10.1007/s00401-013-1123-8