C-terminal and full length TDP-43 specie differ according to FTLD-TDP lesion type but not genetic mutation

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Abstract

The transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein involved in RNA splicing. Abnormally deposited TDP-43 is found in the brains of patients with frontotemporal lobar degeneration (FTLD). Different morphological characteristics of TDP-43 immunoreactive inclusions define the different variants of FTLD-TDP. Little is known about the relationships between TDP-43 specie (phosphorylated TDP-43, C-terminal fragments and full length TDP-43) and lesion types. Using novel antibodies that recognize phosphorylated TDP-43 (pTDP-43), a neoepitope in the C-terminal fragment of TDP-43 (cTDP-43) and the N-terminal, i.e. full length (nTDP-43) we assess the relative burden of pTDP-43, cTDP-43 and nTDP-43 in 8 different lesion types across FTLD-TDP type A-C. These include neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions, fine neurites of the hippocampus, peri-vascular inclusions, Pick body-like inclusions, long thick dystrophic neurites and granular pre-inclusions. We also assess for associations with progranulin (GRN) and C9ORF72 genetic mutations. For all eight lesion types, the highest burden was observed for pTDP-43. In six of the eight lesions studied, cTDP-43 burden was greater than nTDP-43 burden. However, we observed a higher burden of nTDP-43 to cTDP-43 for pre-inclusions. We also noted an equal-to-slightly higher burden of nTDP-43 to cTDP-43 for peri-vascular inclusions. There was not strong evidence for associations to be driven by mutation status although for neuronal cytoplasmic inclusions and dystrophic neurites GRN+ cases had higher burden of pTDP-43, cTDP-43 and nTDP-43 compared to GRN- cases, with nTDP-43 inclusions only observed in GRN+ cases. In addition, for pre-inclusions, cTDP-43 and nTDP-43 burden tended to be higher in C9ORF72- cases compared to C9ORF72+ cases, although this was not the case for pTDP-43. There is clear evidence that phosphorylation and C terminal fragments play an important role in lesion formation in FTLD-TDP. However, for some inclusions, particularly pre-inclusions, full-length TDP-43 appears to be playing a role.

Original languageEnglish (US)
Number of pages1
JournalActa Neuropathologica Communications
Volume7
Issue number1
DOIs
StatePublished - Jul 2 2019

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Frontotemporal Lobar Degeneration
Neurites
Inclusion Bodies
Mutation
Blood Vessels
RNA Splicing
Intranuclear Inclusion Bodies
DNA-Binding Proteins
Hippocampus
Phosphorylation
Antibodies
Brain
Proteins

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

@article{e05ef731669b486bab8a703f7282ce5f,
title = "C-terminal and full length TDP-43 specie differ according to FTLD-TDP lesion type but not genetic mutation",
abstract = "The transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein involved in RNA splicing. Abnormally deposited TDP-43 is found in the brains of patients with frontotemporal lobar degeneration (FTLD). Different morphological characteristics of TDP-43 immunoreactive inclusions define the different variants of FTLD-TDP. Little is known about the relationships between TDP-43 specie (phosphorylated TDP-43, C-terminal fragments and full length TDP-43) and lesion types. Using novel antibodies that recognize phosphorylated TDP-43 (pTDP-43), a neoepitope in the C-terminal fragment of TDP-43 (cTDP-43) and the N-terminal, i.e. full length (nTDP-43) we assess the relative burden of pTDP-43, cTDP-43 and nTDP-43 in 8 different lesion types across FTLD-TDP type A-C. These include neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions, fine neurites of the hippocampus, peri-vascular inclusions, Pick body-like inclusions, long thick dystrophic neurites and granular pre-inclusions. We also assess for associations with progranulin (GRN) and C9ORF72 genetic mutations. For all eight lesion types, the highest burden was observed for pTDP-43. In six of the eight lesions studied, cTDP-43 burden was greater than nTDP-43 burden. However, we observed a higher burden of nTDP-43 to cTDP-43 for pre-inclusions. We also noted an equal-to-slightly higher burden of nTDP-43 to cTDP-43 for peri-vascular inclusions. There was not strong evidence for associations to be driven by mutation status although for neuronal cytoplasmic inclusions and dystrophic neurites GRN+ cases had higher burden of pTDP-43, cTDP-43 and nTDP-43 compared to GRN- cases, with nTDP-43 inclusions only observed in GRN+ cases. In addition, for pre-inclusions, cTDP-43 and nTDP-43 burden tended to be higher in C9ORF72- cases compared to C9ORF72+ cases, although this was not the case for pTDP-43. There is clear evidence that phosphorylation and C terminal fragments play an important role in lesion formation in FTLD-TDP. However, for some inclusions, particularly pre-inclusions, full-length TDP-43 appears to be playing a role.",
author = "Josephs, {Keith Anthony} and Zhang, {Yong Jie} and Matthew Baker and Rademakers, {Rosa V} and Leonard Petrucelli and Dickson, {Dennis W}",
year = "2019",
month = "7",
day = "2",
doi = "10.1186/s40478-019-0755-x",
language = "English (US)",
volume = "7",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "BioMed Central",
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TY - JOUR

T1 - C-terminal and full length TDP-43 specie differ according to FTLD-TDP lesion type but not genetic mutation

AU - Josephs, Keith Anthony

AU - Zhang, Yong Jie

AU - Baker, Matthew

AU - Rademakers, Rosa V

AU - Petrucelli, Leonard

AU - Dickson, Dennis W

PY - 2019/7/2

Y1 - 2019/7/2

N2 - The transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein involved in RNA splicing. Abnormally deposited TDP-43 is found in the brains of patients with frontotemporal lobar degeneration (FTLD). Different morphological characteristics of TDP-43 immunoreactive inclusions define the different variants of FTLD-TDP. Little is known about the relationships between TDP-43 specie (phosphorylated TDP-43, C-terminal fragments and full length TDP-43) and lesion types. Using novel antibodies that recognize phosphorylated TDP-43 (pTDP-43), a neoepitope in the C-terminal fragment of TDP-43 (cTDP-43) and the N-terminal, i.e. full length (nTDP-43) we assess the relative burden of pTDP-43, cTDP-43 and nTDP-43 in 8 different lesion types across FTLD-TDP type A-C. These include neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions, fine neurites of the hippocampus, peri-vascular inclusions, Pick body-like inclusions, long thick dystrophic neurites and granular pre-inclusions. We also assess for associations with progranulin (GRN) and C9ORF72 genetic mutations. For all eight lesion types, the highest burden was observed for pTDP-43. In six of the eight lesions studied, cTDP-43 burden was greater than nTDP-43 burden. However, we observed a higher burden of nTDP-43 to cTDP-43 for pre-inclusions. We also noted an equal-to-slightly higher burden of nTDP-43 to cTDP-43 for peri-vascular inclusions. There was not strong evidence for associations to be driven by mutation status although for neuronal cytoplasmic inclusions and dystrophic neurites GRN+ cases had higher burden of pTDP-43, cTDP-43 and nTDP-43 compared to GRN- cases, with nTDP-43 inclusions only observed in GRN+ cases. In addition, for pre-inclusions, cTDP-43 and nTDP-43 burden tended to be higher in C9ORF72- cases compared to C9ORF72+ cases, although this was not the case for pTDP-43. There is clear evidence that phosphorylation and C terminal fragments play an important role in lesion formation in FTLD-TDP. However, for some inclusions, particularly pre-inclusions, full-length TDP-43 appears to be playing a role.

AB - The transactive response DNA binding protein of 43 kDa (TDP-43) is an intranuclear protein involved in RNA splicing. Abnormally deposited TDP-43 is found in the brains of patients with frontotemporal lobar degeneration (FTLD). Different morphological characteristics of TDP-43 immunoreactive inclusions define the different variants of FTLD-TDP. Little is known about the relationships between TDP-43 specie (phosphorylated TDP-43, C-terminal fragments and full length TDP-43) and lesion types. Using novel antibodies that recognize phosphorylated TDP-43 (pTDP-43), a neoepitope in the C-terminal fragment of TDP-43 (cTDP-43) and the N-terminal, i.e. full length (nTDP-43) we assess the relative burden of pTDP-43, cTDP-43 and nTDP-43 in 8 different lesion types across FTLD-TDP type A-C. These include neuronal cytoplasmic inclusions, dystrophic neurites, neuronal intranuclear inclusions, fine neurites of the hippocampus, peri-vascular inclusions, Pick body-like inclusions, long thick dystrophic neurites and granular pre-inclusions. We also assess for associations with progranulin (GRN) and C9ORF72 genetic mutations. For all eight lesion types, the highest burden was observed for pTDP-43. In six of the eight lesions studied, cTDP-43 burden was greater than nTDP-43 burden. However, we observed a higher burden of nTDP-43 to cTDP-43 for pre-inclusions. We also noted an equal-to-slightly higher burden of nTDP-43 to cTDP-43 for peri-vascular inclusions. There was not strong evidence for associations to be driven by mutation status although for neuronal cytoplasmic inclusions and dystrophic neurites GRN+ cases had higher burden of pTDP-43, cTDP-43 and nTDP-43 compared to GRN- cases, with nTDP-43 inclusions only observed in GRN+ cases. In addition, for pre-inclusions, cTDP-43 and nTDP-43 burden tended to be higher in C9ORF72- cases compared to C9ORF72+ cases, although this was not the case for pTDP-43. There is clear evidence that phosphorylation and C terminal fragments play an important role in lesion formation in FTLD-TDP. However, for some inclusions, particularly pre-inclusions, full-length TDP-43 appears to be playing a role.

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U2 - 10.1186/s40478-019-0755-x

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