期刊
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
卷 81, 期 4, 页码 271-281出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/jnen/nlac015
关键词
Amyotrophic lateral sclerosis; Diffuse punctate cytoplasmic staining; Morphology; TDP-43; Ribosome; Rough endoplasmic reticulum
资金
- JSPS KAKENHI [20K16592]
- Karoji Memorial Fund for Medical Research
- Grants-in-Aid for Scientific Research [20K16592] Funding Source: KAKEN
DPCS is the primary manifestation of short-duration ALS, with a high density and an inverse correlation with disease duration. DPCS is associated with nonfibrillar TDP-43 localized to the ribosomes of the rough endoplasmic reticulum.
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.
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