TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing
TDP-43 in ubiquitinated inclusions in the inferior olives in frontotemporal lobar degeneration and in other neurodegenerative diseases: a degenerative process distinct from normal ageing
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DOI：
10.1007/s00401-009-0526-z
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发表时间：
2009-09-01
影响因子：
12.7
通讯作者：
Mann, David M. A.
中科院分区：
文献类型：
--
作者：
Davidson, Yvonne;Amin, Hanan;Mann, David M. A.
泛素免疫反应性 (UBQ-ir) 内含物在 37/48 (77%) 额颞叶变性 (FTLD) 患者、10/11 (91%) 运动神经元疾病 (MND) 患者、5/5 (100%) 阿尔茨海默病 (AD) 患者中不同程度地存在于下橄榄核 (ION) 中， 5/7（71%）患有路易体痴呆的患者，13/19（68%）患有帕金森病的患者，11/11（100%）患有进行性核上性麻痹的患者，2/6（33%）患有多系统萎缩症的患者，1/3（33%）患有亨廷顿病的患者以及14/14（100%）正常老年对照受试者。在 FTLD 中，26/32 (81%) 的 FTLD-U 患者、10/15 (67%) 的 tau 蛋白病患者以及一名缺乏独特组织学的痴呆患者中存在 UBQ-ir 包涵体。在 13 名 FTLD-U 患者、一名 AD 患者和 2 名 MND 患者中，UBQ-ir 包涵体具有圆形、针状或绞纱型外观，并且这些也具有 TDP-43 免疫反应性 (TDP-43-ir)。在所有诊断组的所有其他受影响患者以及对照受试者中，UBQ-ir 神经元细胞质内含物 (NCI) 均为聚集型，类似于一簇大颗粒或小球，但从来不是 TDP-43-ir。在 13 名患有针状 NCI 的 FTLD-U 患者中，有 3 名也存在聚集性 NCI，但位于不同的细胞中。 UBQ 和 TDP-43 的双标记免疫组织化学和共聚焦显微镜证实，只有 FTLD-U、AD 和 MND 患者的针状 UBQ-ir 包涵体含有 TDP-43，尽管在这些患者中偶尔存在非 UBQ-ir 的 TDP-43 免疫反应性包涵体。当存在 TDP-43 细胞质包涵体时，FTLD-U、AD 或 MND 中的 ION 中不存在核 TDP-43 免疫反应性，但在具有 UBQ-ir、TDP-43 阴性包涵体的神经元中仍然存在。 UBQ-ir、TDP-43 阴性包涵体中的靶蛋白仍然未知，但目前的研究表明这不是 tau、神经丝或互连蛋白。这些 TDP-43 阴性的 UBQ-ir 内含物似乎与衰老的关系比与神经变性的关系更大，并且没有明显的诊断意义。导致它们形成的病理生理机制以及它们的存在可能对神经细胞功能产生的任何后果仍然未知。
Ubiquitin immunoreactive (UBQ-ir) inclusions were present to variable extents in the inferior olivary nucleus (ION) in 37/48 (77%) patients with frontotemporal lobar degeneration (FTLD), in 10/11 (91%) patients with motor neurone disease (MND), in 5/5 (100%) patients with Alzheimer's disease (AD), 5/7 (71%) patients with dementia with Lewy bodies, 13/19 (68%) patients with Parkinson's disease, 11/11(100%) patients with Progressive Supranuclear Palsy, 2/6 (33%) patients with Multisystem Atrophy, 1/3 (33%) patients with Huntington's disease and in 14/14 (100%) normal elderly control subjects. In FTLD, UBQ-ir inclusions were present in 26/32 (81%) patients with FTLD-U, in 10/15 (67%) patients with tauopathy, and in the single patient with Dementia Lacking Distinctive Histology. In 13 FTLD-U patients, and in a single AD and in 2 MND patients, the UBQ-ir inclusions had a rounded, spicular or skein-type appearance, and these were also TDP-43 immunoreactive (TDP-43-ir). In all other affected patients in all diagnostic groups, and in control subjects, the UBQ-ir neuronal cytoplasmic inclusions (NCI) were of a conglomerated type, resembling a cluster of large granules or globules, but were never TDP-43-ir. In 3 of the 13 FTLD-U patients with spicular NCI, conglomerated NCI were also present but in separate cells. Double-labelling immunohistochemistry, and confocal microscopy, for UBQ and TDP-43 confirmed that only the spicular UBQ-ir inclusions in patients with FTLD-U, AD and MND contained TDP-43, though in these patients there were occasional TDP-43 immunoreactive inclusions that were not UBQ-ir. Nuclear TDP-43 immunoreactivity was absent in ION in FTLD-U, AD or MND when TDP-43 cytoplasmic inclusions were present, but remained in neurones with UBQ-ir, TDP-43 negative inclusions. The target protein within the UBQ-ir, TDP-43-negative inclusions remains unknown, but present studies indicate that this is not tau, neurofilament or internexin proteins. These TDP-43 negative, UBQ-ir inclusions appear to be more related to ageing than neurodegeneration, and are without apparent diagnostic significance. The pathophysiological mechanism leading to their formation, and any consequences their presence may have on nerve cell function, remain unknown.