Distinct TDP-43 inclusion morphologies in frontotemporal lobar degeneration with and without amyotrophic lateral sclerosis

Rachel H Tan,Glenda M Halliday,Woojin S Kim,Yue Yang,Carol Dobson-Stone,John B Kwok,Matthew C Kiernan

doi:10.1186/s40478-017-0480-2

Abstract

The identification of the TAR DNA-binding protein 43 (TDP-43) as the ubiquitinated cytoplasmic inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) confirmed that these two diseases share similar mechanisms, likely to be linked to the abnormal hyperphosphorylation, ubiquitination and cleavage of pathological TDP-43. Importantly however, a quantitative analysis of TDP-43 inclusions in predilection cortical regions of FTLD, FTLD-ALS and ALS cases has not been undertaken. The present study set out to assess this and demonstrates that distinct TDP-43 inclusion morphologies exist in the anterior cingulate cortex, but not the motor cortex of FTLD and FTLD-ALS. Specifically, in the anterior cingulate cortex of FTLD cases, significant rounded TDP-43 inclusions and rare circumferential TDP-43 inclusions were identified. In contrast, FTLD-ALS cases revealed significant circumferential TDP-43 inclusions and rare rounded TDP-43 inclusions in the anterior cingulate cortex. Distinct TDP-43 inclusion morphologies in the anterior cingulate cortex of FTLD and FTLD-ALS may be linked to heterogeneity in the ubiquitination of pathological TDP-43 inclusions, with the present study providing evidence to suggest the involvement of distinct pathomechanisms in these two overlapping clinical syndromes.

Highlights

Neuronal cytoplasmic aggregates containing the nuclear TAR DNA-binding protein 43 (TDP-43) are characteristically observed in the cortical neurons of frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLDTDP), and in the lower motor neurons of cases with amyotrophic lateral sclerosis (ALS)
Regional TDP-43 morphology TDP-43 pathology was identified in the anterior cingulate cortex of 87% ALS (n = 13) and all other cases, and in the Clinicopathological and genetic comparisons Previous studies [30] have shown that the burden of TDP43 pathology in the anterior cingulate cortex but not motor cortex differentiates bvFTD from ALS cases
Analysis of the morphology of the TDP-43 inclusions in the anterior cingulate cortex from the present series demonstrated significant differences across clinicopathological groups (F(2, 52) > 4.3, p < 0.05) with more circumferential TDP-43 inclusions in FTLD-ALS cases compared to ALS and FTLD cases and significantly more rounded TDP-43 inclusions in FTLD cases compared to ALS and FTLD-ALS cases (Fig. 2)

Summary

Introduction

Neuronal cytoplasmic aggregates containing the nuclear TAR DNA-binding protein 43 (TDP-43) are characteristically observed in the cortical neurons of frontotemporal lobar degeneration (FTLD) with TDP-43 pathology (FTLDTDP), and in the lower motor neurons of cases with amyotrophic lateral sclerosis (ALS). The presence of this shared pathological protein has reinforced the theory that FTLD and ALS represent two ends of a disease continuum, with recent studies attributing the manifestation of this pathological protein in two distinct clinical syndromes to its accumulation in key brain regions [1, 8, 12, 13, 25, 30]. The present study set out to do this in order to determine if cortical TDP-43 inclusion morphology is similar in these three clinicopathological groups believed to represent a disease continuum

Methods

Results

Discussion

Conclusion