Lack of TAR‐DNA binding protein‐43 (TDP‐43) pathology in human prion diseases

A M Isaacs,J M Linehan,S Brandner,C Powell,J Collinge,T E Webb

doi:10.1111/j.1365-2990.2008.00963.x

Abstract

AimsTAR-DNA binding protein-43 (TDP-43) is the major ubiquitinated protein in the aggregates in frontotemporal dementia with ubiquitin-positive, tau-negative inclusions and motor neurone disease. Abnormal TDP-43 immunoreactivity has also been described in Alzheimer's disease, Lewy body diseases and Guam parkinsonism–dementia complex. We therefore aimed to determine whether there is TDP-43 pathology in human prion diseases, which are characterised by variable deposition of prion protein (PrP) aggregates in the brain as amyloid plaques or more diffuse deposits.Material and methodsTDP-43, ubiquitin and PrP were analysed by immunohistochemistry and double-labelling immunofluorescence, in sporadic, acquired and inherited forms of human prion disease.ResultsMost PrP plaques contained ubiquitin, while synaptic PrP deposits were not associated with ubiquitin. No abnormal TDP-43 inclusions were identified in any type of prion disease case, and TDP-43 did not co-localize with ubiquitin-positive PrP plaques or with diffuse PrP aggregates.ConclusionsThese data do not support a role for TDP-43 in prion disease pathogenesis and argue that TDP-43 inclusions define a distinct group of neurodegenerative disorders.

Highlights

TAR-DNA binding protein-43 (TDP-43) has recently been identified as the major protein in the ubiquitinated inclusions that characterize frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) and motor neurone disease (MND) [1]
We initially examined prion protein (PrP) and ubiquitin immunoreactivity in the frontal cortex of a variety of inherited prion disease cases as well as sporadic, iatrogenic and variant Creutzfeldt–Jakob disease (CJD) samples
We scored the abundance of PrP plaques and diffuse PrP aggregates for each case in a semi-quantitative assessment, and analysed ubiquitin pathology in these scored cases

Summary

Introduction

TAR-DNA binding protein-43 (TDP-43) has recently been identified as the major protein in the ubiquitinated inclusions that characterize frontotemporal lobar degeneration with ubiquitin-positive, tau-negative inclusions (FTLD-U) and motor neurone disease (MND) [1]. Occasional TDP-43 staining has been noted in neurofibrillary tangles [2,3,7] and in corticobasal degeneration [7] and Pick’s disease brains [7,8]. These findings show that a number of neurodegenerative diseases characterized by protein aggregation have pathological TDP-43 immunoreactivity, prompting us to look in prion disease brains, which contain protein aggregates. The inherited cases have been classified as Gerstmann– Sträussler–Scheinker disease (GSS), fatal familial insomnia (FFI) or CJD; the range of clinical presentations, even within families with the same PRNP mutation [18,19,20,21,22], has led to sub-classification based on the PRNP mutation and the genotype at codon 129 [20,23]

Methods

Results

Conclusion