p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS
p62 positive, TDP-43 negative, neuronal cytoplasmic and intranuclear inclusions in the cerebellum and hippocampus define the pathology of C9orf72-linked FTLD and MND/ALS
复制标题
DOI：
10.1007/s00401-011-0911-2
复制
发表时间：
2011-12-01
影响因子：
12.7
通讯作者：
Shaw, Christopher E.
中科院分区：
文献类型：
--
作者：
Al-Sarraj, Safa;King, Andrew;Shaw, Christopher E.
含有磷酸化TDP-43（p-TDP-43）的神经元胞质内含物（NCI）是运动神经元疾病/肌萎缩侧索硬化（MND/ALS）和FTLD-TDP的病理标志。脑和脊髓中的绝大多数NCIs也标记为泛素和p62，然而，我们先前报道了TDP-43蛋白病患者的一个子集，他们在小脑和海马中具有不寻常的和丰富的p62阳性，TDP-43阴性包涵体。在此，我们试图确定这些病例是否携带C9 orf 72中的六核苷酸重复扩增。对36例MND/ALS、FTLD-MND/ALS和FTLD-TDP病例及4例对照进行了重复引物PCR检测。检测到14个具有重复扩增的个体。在所有14例扩增突变病例中，海马锥体细胞层中均存在大量球形和星形p62阳性NCI，其中绝大多数为p-TDP-43阴性。14例小脑颗粒层和分子层及12例浦肯野细胞中均有大量p62阳性细胞，但仅1例颗粒层p-TDP-43阳性。12/14例海马锥体细胞层和6/14例小脑颗粒层可见大量p62阳性、p-TDP-43阴性的神经元核内包涵体（NIIs）。这种不寻常的夹杂物组合似乎是C9 orf 72重复扩增阳性MND/ALS和FTLD-TDP的特异性特征，我们认为它们形成了TDP-43蛋白病的病理学不同子集。我们的研究结果表明，TDP-43以外的蛋白质结合p62和聚集在响应突变，这可能在神经退行性变中发挥机械作用。
Neuronal cytoplasmic inclusions (NCIs) containing phosphorylated TDP-43 (p-TDP-43) are the pathological hallmarks of motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) and FTLD-TDP. The vast majority of NCIs in the brain and spinal cord also label for ubiquitin and p62, however, we have previously reported a subset of TDP-43 proteinopathy patients who have unusual and abundant p62 positive, TDP-43 negative inclusions in the cerebellum and hippocampus. Here we sought to determine whether these cases carry the hexanucleotide repeat expansion in C9orf72. Repeat primer PCR was performed in 36 MND/ALS, FTLD-MND/ALS and FTLD-TDP cases and four controls. Fourteen individuals with the repeat expansion were detected. In all the 14 expansion mutation cases there were abundant globular and star-shaped p62 positive NCIs in the pyramidal cell layer of the hippocampus, the vast majority of which were p-TDP-43 negative. p62 positive NCIs were also abundant in the cerebellar granular and molecular layers in all cases and in Purkinje cells in 12/14 cases but they were only positive for p-TDP-43 in the granular layer of one case. Abundant p62 positive, p-TDP-43 negative neuronal intranuclear inclusions (NIIs) were seen in 12/14 cases in the pyramidal cell layer of the hippocampus and in 6/14 cases in the cerebellar granular layer. This unusual combination of inclusions appears pathognomonic for C9orf72 repeat expansion positive MND/ALS and FTLD-TDP which we believe form a pathologically distinct subset of TDP-43 proteinopathies. Our results suggest that proteins other than TDP-43 are binding p62 and aggregating in response to the mutation which may play a mechanistic role in neurodegeneration.