Kikuchi Kenji, Arawaka Shigeki, Koyama Shingo, Kimura Hideki, Ren Chang-Hong, Wada Manabu, Kawanami Toru, Kurita Keiji, Daimon Makoto, Kawakatsu Shinobu, Kadoya Toshihiko, Goto Kaoru, Kato Takeo
Third Department of Internal Medicine, Yamagata University School of Medicine, Japan.
Biochem Biophys Res Commun. 2003 Aug 29;308(3):646-54. doi: 10.1016/s0006-291x(03)01391-3.
The deposition of aggregated tau in cytoplasmic inclusions is one of the common neuropathological features in various dementing neurodegenerative disorders. At present, it remains unclear whether tau inclusions exert neurotoxicity or they are simply the consequence of neurodegeneration. In our approach for the analysis of the composition of tau inclusions, we detected the intense binding of anti-diacylglycerol kinase-zeta (DGK-zeta) antibodies to Pick bodies (PBs), which represent tau inclusions in Pick's disease. The polyclonal antibodies were found to cross-react with a 21-kDa protein, but not with tau or ubiquitin, on Western blots of normal human brain extracts. Analysis of the 21-kDa protein by two-dimensional-gel electrophoresis and mass-spectrometry revealed that the protein is an N-terminal fragment of proSAAS (a human granin-like neuroendocrine peptide precursor). Our results suggest that sequestration of the N-terminal fragment of proSAAS in intracellular PBs may cause a functional disturbance of neurons in Pick's disease.
聚集的tau蛋白在细胞质内含物中的沉积是各种痴呆性神经退行性疾病常见的神经病理学特征之一。目前，tau蛋白内含物是否发挥神经毒性作用，或者它们仅仅是神经退行性变的结果，仍不清楚。在我们分析tau蛋白内含物组成的方法中，我们检测到抗二酰甘油激酶ζ（DGK-ζ）抗体与Pick小体（PBs）有强烈结合，Pick小体代表Pick病中的tau蛋白内含物。在正常人脑提取物的蛋白质免疫印迹中，发现该多克隆抗体与一种21 kDa的蛋白质发生交叉反应，但不与tau蛋白或泛素发生反应。通过二维凝胶电泳和质谱分析该21 kDa蛋白质，结果显示该蛋白质是proSAAS（一种人颗粒蛋白样神经内分泌肽前体）的N端片段。我们的结果表明，proSAAS的N端片段在细胞内Pick小体中的隔离可能导致Pick病中神经元的功能紊乱。
