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.
Highlights
The TAR DNA binding protein of 43 kDa (TDP-43) is a nuclear protein that is involved with RNA splicing and transcription repression [5, 6]
TDP-43 immunohistochemistry & semi-quantitation In all 24 cases we performed serial sectioning and TDP43 immunohistochemistry with four different TDP-43 antibodies: phosphorylated TDP-43 antibody that recognizes TDP-43 with phosphorylated epitopes; anti TDP-43 antibody that recognizes a neoepitope in the C terminal fragment of cleaved TDP43(cTDP-43) (MC2085, 1:2500 rabbit polyclonal, gift from Leonard Petrucelli, Mayo Clinic) [46]; anti TDP-43 antibody that recognizes an epitope in the amino terminus (MC1079; 1:2500 rabbit polyclonal, gift from Leonard Petrucelli, Mayo Clinic) [46] and a rabbit polyclonal anti-TDP-43 antibody (ProteinTech Group; Chicago IL; dilution 1:3000) which is a commercially available antibody
Hippocampal sclerosis was observed in all frontotemporal lobar degeneration (FTLD)-TDP type A cases, but less than 25% of type B and C cases
Summary
The TAR DNA binding protein of 43 kDa (TDP-43) is a nuclear protein that is involved with RNA splicing and transcription repression [5, 6]. Little is known regarding differences in phosphorylation specie, Cterminal specie and full length TDP-43 by lesion type. There is heterogeneity in mutation status in FTLD-TDP with some cases being association with mutations in either the progranulin (GRN) gene [2, 12] or with mutations in the C9ORF72 gene [13, 36] while other cases are not associated with either mutation. GRN mutations are associated with FTLD-TDP type A and neuronal intranuclear inclusions (NII) [16, 23] while C9ORF72 mutations are associated with FTLD-TDP type B and granular preinclusions [19, 36, 37]. Little is known about the association between mutation status and TDP-43 specie
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