TDP-43 突变转基因小鼠的性别特异性早期视网膜功能障碍。

Sex-Specific Early Retinal Dysfunction in Mutant TDP-43 Transgenic Mice.

机构信息

Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.

School of Pharmacy, University of Eastern Finland, Kuopio, Finland.

出版信息

J Alzheimers Dis. 2024;97(2):927-937. doi: 10.3233/JAD-231102.

DOI:10.3233/JAD-231102

PMID:38143367

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11174142/

Abstract

BACKGROUND

Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases.

OBJECTIVE

While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the assessment also of retinal changes during the disease progression.

METHODS

We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings.

RESULTS

At 3-4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender.

CONCLUSIONS

Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions.

摘要

背景

越来越多的证据表明，视网膜在神经退行性疾病中受损。TAR DNA 结合蛋白 43（TDP-43）的显性突变导致肌萎缩侧索硬化症（ALS），TDP-43 在细胞质中的积累是 ALS、额颞叶痴呆（FTD）和许多其他神经退行性疾病的病理标志。

目的

虽然表达致病人类 TDP-43 M337V 突变的纯合转基因小鼠（TDP-43M337V 小鼠）会过早死亡，但杂合 TDP-43M337V 小鼠不会突然死亡，但它们表现出年龄依赖性的运动协调和认知缺陷。本研究旨在利用杂合 TDP-43M337V 小鼠作为一种有价值的 ALS/FTD 疾病模型，评估疾病进展过程中的视网膜变化。

方法

我们通过全视野视网膜电图（ERG）记录评估年轻 TDP-43M337V 小鼠的视网膜功能。

结果

在 3-4 个月大时，即 8 个月大脑功能障碍发作之前，年轻雌性 TDP-43M337V 小鼠的视网膜 ERG 反应明显受损，与雄性和同龄非转基因小鼠相比。线粒体已被认为是 TDP-43 的关键靶标。进一步的研究表明，只有在年轻雌性 TDP-43M337V 小鼠的视网膜中才观察到线粒体动力学和生物能量关键调节剂的显着变化，而在两性的大脑中均未观察到这些变化。