Neurological Disorders Group, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdiSSC), Madrid 28040, Spain.
Neurological Disorders Group, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria Hospital Clínico San Carlos (IdiSSC), Madrid 28040, Spain; MRC Harwell Institute, Oxfordshire, UK.
Neurobiol Dis. 2024 Apr;193:106437. doi: 10.1016/j.nbd.2024.106437. Epub 2024 Feb 15.
TDP-43 pathology is found in several neurodegenerative disorders, collectively referred to as "TDP-43 proteinopathies". Aggregates of TDP-43 are present in the brains and spinal cords of >97% of amyotrophic lateral sclerosis (ALS), and in brains of ∼50% of frontotemporal dementia (FTD) patients. While mutations in the TDP-43 gene (TARDBP) are usually associated with ALS, many clinical reports have linked these mutations to cognitive impairments and/or FTD, but also to other neurodegenerative disorders including Parkinsonism (PD) or progressive supranuclear palsy (PSP). TDP-43 is a ubiquitously expressed, highly conserved RNA-binding protein that is involved in many cellular processes, mainly RNA metabolism. To investigate systemic pathological mechanisms in TDP-43 proteinopathies, aiming to capture the pleiotropic effects of TDP-43 mutations, we have further characterised a mouse model carrying a point mutation (M323K) within the endogenous Tardbp gene. Homozygous mutant mice developed cognitive and behavioural deficits as early as 3 months of age. This was coupled with significant brain structural abnormalities, mainly in the cortex, hippocampus, and white matter fibres, together with progressive cortical interneuron degeneration and neuroinflammation. At the motor level, progressive phenotypes appeared around 6 months of age. Thus, cognitive phenotypes appeared to be of a developmental origin with a mild associated progressive neurodegeneration, while the motor and neuromuscular phenotypes seemed neurodegenerative, underlined by a progressive loss of upper and lower motor neurons as well as distal denervation. This is accompanied by progressive elevated TDP-43 protein and mRNA levels in cortex and spinal cord of homozygous mutant mice from 3 months of age, together with increased cytoplasmic TDP-43 mislocalisation in cortex, hippocampus, hypothalamus, and spinal cord at 12 months of age. In conclusion, we find that Tardbp M323K homozygous mutant mice model many aspects of human TDP-43 proteinopathies, evidencing a dual role for TDP-43 in brain morphogenesis as well as in the maintenance of the motor system, making them an ideal in vivo model system to study the complex biology of TDP-43.
TDP-43 病理学存在于几种神经退行性疾病中，统称为“TDP-43 蛋白病”。TDP-43 聚集物存在于 >97%的肌萎缩侧索硬化症（ALS）的大脑和脊髓中，以及约 50%的额颞叶痴呆（FTD）患者的大脑中。虽然 TDP-43 基因（TARDBP）的突变通常与 ALS 相关，但许多临床报告将这些突变与认知障碍和/或 FTD 联系起来，但也与其他神经退行性疾病（包括帕金森病或进行性核上性麻痹）联系起来。TDP-43 是一种广泛表达的、高度保守的 RNA 结合蛋白，参与许多细胞过程，主要是 RNA 代谢。为了研究 TDP-43 蛋白病中的系统性病理机制，旨在捕捉 TDP-43 突变的多效性，我们进一步表征了一种携带内源性 Tardbp 基因点突变（M323K）的小鼠模型。纯合突变小鼠早在 3 个月大时就出现认知和行为缺陷。这与大脑结构的显著异常有关，主要是在皮质、海马体和白质纤维中，以及皮质中间神经元的进行性退化和神经炎症。在运动水平上，大约 6 个月大时出现进行性表型。因此，认知表型似乎具有发育起源，伴有轻度进行性神经退行性变，而运动和神经肌肉表型似乎是神经退行性的，这是由上运动神经元和下运动神经元以及远端去神经支配的进行性丧失所强调的。这伴随着纯合突变小鼠从 3 个月大时皮质和脊髓中 TDP-43 蛋白和 mRNA 水平的逐渐升高，以及 12 个月大时皮质、海马体、下丘脑和脊髓中细胞质 TDP-43 错误定位的增加。总之，我们发现 Tardbp M323K 纯合突变小鼠模型模拟了人类 TDP-43 蛋白病的许多方面，证明 TDP-43 在大脑形态发生以及运动系统的维持中具有双重作用，使其成为研究 TDP-43 复杂生物学的理想体内模型系统。
