Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family
Characterization of ubiquitinated intraneuronal inclusions in a novel Belgian frontotemporal lobar degeneration family
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DOI：
10.1097/01.jnen.0000205147.39210.c7
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发表时间：
2006-03-01
影响因子：
3.2
通讯作者：
Kumar-Singh, Samir
中科院分区：
文献类型：
--
作者：
Pirici, Daniel;Vandenberghe, Rik;Kumar-Singh, Samir
额颞叶变性(FTLD)患者最常见的组织学特征是细胞内含有尚未鉴定的蛋白，这些蛋白可与抗泛素(Ub)抗体反应，但不与tau或突触核蛋白(FTLD-U)反应。我们确定了一个四代比利时FTLD家族，其中8名患者主要遗传FTLD。在1例患者中，我们显示额颞部萎缩，有丝状Ub阳性的细胞内包涵体，没有tau病理或任何可溶性tau水平的改变。我们对包裹体的细胞和亚细胞定位和形态进行了表征。UB阳性包涵体主要见于神经元(97%)，但也见于少突胶质细胞(约2%)和小胶质细胞(约1%)，但不见于星形胶质细胞。在亚细胞定位方面，核内包涵体(INI)的出现频率约为胞浆内包涵体的四倍，尽管后者更具神经元特异性。INI经常出现纺锤形和三维共聚焦重建，发现扁平的叶状结构。在超微结构上，直径为10-18 nm的直丝在核膜附近形成纺锤形的包裹体。仅在少数包涵体中观察到Hsp40、p62和Valosin/p97的染色。鉴于该蛋白的精确性质将有助于确定家族性和更普遍的散发性FTLD-U的发病机制中的共同点。
The most common histologic feature in patients with frontotemporal lobar degeneration (FTLD) is intracellular brain inclusions of yet uncharacterized proteins that react with antiubiquitin (Ub) antibodies, but not with tau or synuclein (FTLD-U). We identified a four-generation Belgian FTLD family in which 8 patients had dominantly inherited FTLD. In one patient, we showed frontotemporal atrophy with filamentous Ub-positive intracellular inclusions in absence of tau pathology or any alterations in the levels of soluble tau. We characterized the cellular and subcellular localization and morphology of the inclusions. Ub-positive inclusions predominantly occurred within neurons (> 97%), but were also observed within oligodendroglia (approximately 2%) and microglia (< 1%), but not within astroglia. Regarding the subcellular localization, the intranuclear inclusions (INI) were up to approximately four-fold more frequent than the cytoplasmic inclusions, although the latter were more specific to neurons. The INIs frequently appeared spindle-shaped and 3-dimensional confocal reconstructions identified flattened, leaf-like structures. Ultrastructurally, straight 10- to 18-nm-diameter filaments constituted the spindle-shaped inclusions that occurred in close proximity to the nuclear membrane. Staining for HSP40, p62, and valosin/p97 was observed in only a minority of the inclusions. Whereas the precise nature of the protein would be helpful in identifying a common denominator in the pathogenesis of familial and the more prevalent sporadic FTLD-U.