Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease
Severe subcortical TDP-43 pathology in sporadic frontotemporal lobar degeneration with motor neuron disease
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DOI：
10.1007/s00401-007-0315-5
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发表时间：
2008-01-01
影响因子：
12.7
通讯作者：
Trojanowski, John Q.
中科院分区：
文献类型：
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作者：
Brandmeir, Nicholas J.;Geser, Felix;Trojanowski, John Q.
近期，一种分子量为43kDa的核内TAR DNA结合蛋白TDP - 43被确定为额颞叶变性伴泛素化包涵体（FTLD - U）、伴运动神经元病的额颞叶变性（FTLD - MND）以及肌萎缩侧索硬化症中的主要致病蛋白。到目前为止，散发性FTLD - MND中的TDP - 43病理改变仅在部分中枢神经系统区域有报道。然而，这种病变分布不足以解释FTLD - MND的所有临床症状，并且整个大脑中TDP - 43病理改变的程度仍然未知。因此，作为一项初步研究，我们对两例临床诊断为FTLD - MND的病例和两例对照受试者进行了全脑免疫组化扫描。我们在多个脑区发现了神经元和神经胶质TDP - 43病理改变的证据，包括黑质 - 纹状体系统、新皮质和异生皮质脑区，其出现频率、形态和程度各不相同，而在对照组织中未发现。在几个脑区中，一种明显的细胞病理学特征较为突出，即细胞核内缺乏内源性TDP - 43染色，同时伴有弥漫性/颗粒状细胞质染色（“前包涵体”）。这些前包涵体没有或仅有微弱的泛素免疫反应性。虽然发现皮质下或锥体外系区域严重受累的结果强烈提示FTLD - MND是一种TDP - 43多系统蛋白病，而不是一种主要影响皮质和脊髓的疾病，但需要对更大的队列进行更详细的临床病理研究，以充分阐明这种疾病中病理性TDP - 43的分布和严重程度。
Recently, TDP-43, a 43 kDa nuclear TAR DNA-binding protein, was identified as the major disease protein in frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U), FTLD-U with motor neuron disease (FTLD-MND), and amyotrophic lateral sclerosis. To date, TDP-43 pathology in sporadic FTLD-MND has been reported only in select central nervous system areas. However, this distribution of lesions is insufficient to explain all clinical signs of FTLD-MND and the extent of TDP-43 pathology, throughout the brain, remains unknown. Therefore, as a pilot study, we performed an immunohistochemical whole brain scan of two cases diagnosed clinically as FTLD-MND and two control subjects. We found evidence of both neuronal and glial TDP-43 pathology in multiple brain areas including the nigro-striatal system, neo- and allocortical brain areas, with varying frequency, morphology, and degree, and nowhere in control tissue. The finding of a distinct cytopathological profile consisting of a cell nucleus devoid of endogenous TDP-43 staining coupled with diffuse/granular cytoplasmic staining ("pre-inclusion") was prominent in a couple of brain areas. These pre-inclusions were not or only weakly ubiquitin-immunoreactive. While the findings of severe involvement of extracortical or extrapyramidal areas are strongly suggestive for FTLD-MND being a TDP-43 multisystem proteinopathy rather than a disease predominantly affecting the cortex and spinal cord, more detailed clinicopathological studies of larger cohorts are needed to fully elucidate the distribution and severity of pathological TDP-43 in this disease.