Accumulation of Nonfibrillar TDP-43 in the Rough Endoplasmic Reticulum Is the Early-Stage Pathology in Amyotrophic Lateral Sclerosis.
J Neuropathol Exp Neurol
; 81(4): 271-281, 2022 03 29.
Article
de En
| MEDLINE
| ID: mdl-35294549
ABSTRACT
Transactivation response DNA-binding protein 43 (TDP-43)-immunoreactive neuronal cytoplasmic inclusions (NCIs) are the histopathological hallmarks of amyotrophic lateral sclerosis (ALS). They are classified as skein-like inclusions, round inclusions, dot-like inclusions, linear wisps, and diffuse punctate cytoplasmic staining (DPCS). We hypothesized that TDP-43-immunoreactive DPCS may form the early-stage pathology of ALS. Hence, we investigated phosphorylated TDP-43 pathology in the upper and lower motor neurons of patients with ALS and control participants. We designated patients whose disease duration was ≤1 year as short-duration ALS (n = 7) and those whose duration equaled 3-5 years as standard-duration ALS (n = 6). DPCS and skein-like inclusions were the most common NCIs in short-duration and standard-duration ALS, respectively. The density of DPCS was significantly higher in short-duration ALS than that in standard-duration ALS and was inversely correlated with disease duration. DPCS was not ubiquitinated and disappeared after proteinase K treatment, suggesting that it was not aggregated. Immunoelectron microscopy revealed that DPCS corresponded to nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum (ER). These findings suggest that nonfibrillar TDP-43 accumulation in the rough ER is the earliest TDP-43 pathology in ALS, which may be helpful in developing future TDP-43 breakdown strategies for ALS.
Mots clés
Texte intégral:
1
Collection:
01-internacional
Base de données:
MEDLINE
Sujet principal:
Réticulum endoplasmique rugueux
/
Protéines de liaison à l'ADN
/
Sclérose latérale amyotrophique
Limites:
Humans
Langue:
En
Journal:
J Neuropathol Exp Neurol
Année:
2022
Type de document:
Article
Pays d'affiliation:
Japon