Colocalization of TDP-43 and stress granules at the early stage of TDP-43 aggregation in amyotrophic lateral sclerosis

IF 5.8 2区 医学 Q1 CLINICAL NEUROLOGY
Brain Pathology Pub Date : 2023-10-04 DOI:10.1111/bpa.13215
Fumiaki Mori, Hina Yasui, Yasuo Miki, Tomoya Kon, Akira Arai, Hidekachi Kurotaki, Masahiko Tomiyama, Koichi Wakabayashi
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Abstract

TDP-43 aggregates (skeins and round inclusions [RIs]) are frequent histopathological features of amyotrophic lateral sclerosis (ALS). We have shown that diffuse punctate cytoplasmic staining (DPCS) is the earliest pathologic manifestation of TDP-43 in ALS, corresponding to nonfibrillar TDP-43 located in the rough endoplasmic reticulum. Previous in vitro studies have suggested that TDP-43 inclusions may be derived from stress granules (SGs). Therefore, we investigated the involvement of SGs in the formation of TDP-43 inclusions. Formalin-fixed spinal cords of six ALS patients with a disease duration of less than 1 year (short duration), eight patients with a disease duration of 2–5 years (standard duration), and five normal controls were subjected to histopathological examination using antibodies against an SG marker, HuR. In normal controls, the cytoplasm of anterior horn cells was diffusely HuR-positive. In short-duration and standard-duration ALS, the number of HuR-positive anterior horn cells was significantly decreased relative to the controls. DPCS and RIs were more frequent in short-duration ALS than in standard-duration ALS. The majority of DPCS areas and a small proportion of RIs, but not skeins, were positive for HuR. Immunoelectron microscopy showed that ribosome-like granular structures in DPCS areas and RIs were labeled with anti-HuR, whereas skeins were not. These findings suggest that colocalization of TDP-43 and SGs occurs at the early stage of TDP-43 aggregation.

Abstract Image

Abstract Image

肌萎缩侧索硬化症TDP-43聚集早期TDP-43和应激颗粒的共定位。
TDP-43聚集体(骨骼和圆形内含物[RIs])是肌萎缩侧索硬化症(ALS)常见的组织病理学特征。我们已经表明,弥漫性点状细胞质染色(DPCS)是ALS中TDP-43最早的病理表现,对应于位于粗糙内质网中的非纤维TDP-43。先前的体外研究表明,TDP-43内含物可能来源于应力颗粒(SG)。因此,我们研究了SGs在TDP-43夹杂物形成中的作用。福尔马林固定治疗6例病程小于1年的ALS患者的脊髓 年(短期),8名患者的病程为2-5 年(标准持续时间),并且使用针对SG标记HuR的抗体对五个正常对照进行组织病理学检查。在正常对照中,前角细胞的细胞质呈弥漫性HuR阳性。在短时间和标准时间ALS中,HuR阳性前角细胞的数量相对于对照组显著减少。DPCS和RIs在短时间ALS中的发生率高于标准时间ALS。大多数DPCS区域和一小部分RI(但不是骨架)对HuR呈阳性。免疫电子显微镜显示,DPCS区域和RIs中的核糖体样颗粒结构被抗HuR标记,而骨架蛋白则没有。这些发现表明TDP-43和SG的共定位发生在TDP-43聚集的早期阶段。
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来源期刊
Brain Pathology
Brain Pathology 医学-病理学
CiteScore
13.20
自引率
3.10%
发文量
90
审稿时长
6-12 weeks
期刊介绍: Brain Pathology is the journal of choice for biomedical scientists investigating diseases of the nervous system. The official journal of the International Society of Neuropathology, Brain Pathology is a peer-reviewed quarterly publication that includes original research, review articles and symposia focuses on the pathogenesis of neurological disease.
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