Maturation process of TDP-43-positive neuronal cytoplasmic inclusions in amyotrophic lateral sclerosis with and without dementia

Abstract

To elucidate the maturation process of TDP-43-positive neuronal inclusions, we immunohistochemically and immunoelectron-microscopically examined multiple areas from the brain and spinal cord from ten patients with amyotrophic lateral sclerosis (ALS) and 25 control subjects. TDP-43 immunohistochemistry demonstrated three types of inclusions in ALS: skein-like, round, and dot-like inclusions. Skein-like inclusions were found in all cases of ALS. Dot-like inclusions were found in the anterior horn in seven cases of ALS, all of whom had round inclusions, but not in cases without round inclusions. In addition, careful examination revealed two types of diffuse punctate cytoplasmic staining: linear wisps and punctate granules. Linear wisps were present in all cases of ALS but in none of 25 controls. In contrast, punctate granules were detected in all cases of ALS as well as in five of 13 normal and in seven of 12 diseased controls. Immunoelectron-microscopy revealed that skein-like inclusions consisted of granule-associated parallel filaments. Round and dot-like inclusions were composed of granulo-filamentous structures. However, punctate granules corresponded to the mitochondria and were not immunostained with anti-ubiquitin, indicating that punctate granules represent cross-reaction. We assumed that linear wisps ("fine skein") aggregate as thicker and longer threads ("coarse skein"), whereas round inclusions arise from dot-like inclusions. These findings suggest that there are differences in the formation process between skein-like and round inclusions, despite the antigenic and ultrastructural similarities.

Modeling ALS and FTLD proteinopathies in yeast: An efficient approach for studying protein aggregation and toxicity

“…82 While SOD1 and TDP-43 protein inclusions do not possess many of the defining characteristic features of amyloid, 80 they have been described as having a fiber-like morphology. [83][84][85] Similar observations were reported for FUS inclusions. 86,87 It is conceivable that pathological aggregates of TDP-43 and FUS might also share a common seeding mechanism of propagation with cell-to-cell transmission, which would explain the rapid progressive nature of ALS.…”

Spreading of pathology in neurodegenerative diseases: a focus on human studies

“…These studies noted that pathological lesions develop at different CNS sites sequentially, and that disease progression is associated with an increase in the size of aggregates and an increase in the number of cells showing pathological inclusions at these sites 66,67 . Such a stereotypical pathology pattern was first established for AD, in which tau aggregates are found first in the locus coeruleus of the pontine tegmentum 68 and then in the transentorhinal cortex of the anteromedial temporal lobe (FIG.…”

Prion-like disorders: blurring the divide between transmissibility and infectivity

“…2E) are required for toxicity in both yeast and neuroblastoma cell lines (Johnson et al, 2008;Zhang et al, 2009). In isolation, pure TDP-43 is intrinsically aggregation-prone and rapidly assembles into aggregated species that are morphologically very similar to the aggregates that accumulate in the degenerating neurons of ALS patients (Johnson et al, 2009;Lin and Dickson, 2008;Mori et al, 2008;Nishihira et al, 2008). Here, too, the C-terminal prion domain is crucial: deletion of this domain precludes aggregation (Johnson et al, 2009).…”