Synaptojanin 1 (SYNJ1) is a brain-enriched lipid phosphatase critically involved in autophagosomal/endosomal trafficking, synaptic vesicle recycling and metabolism of phosphoinositides. Previous studies suggest that SYNJ1 polymorphisms have significant impact on the age of onset of Alzheimer’s disease (AD) and that SYNJ1 is involved in amyloid-induced toxicity. Yet SYNJ1 protein level and cellular localization in post-mortem human AD brain tissues have remained elusive. This study aimed to examine whether SYNJ1 localization and expression are altered in post-mortem AD brains. We found that SYNJ1 is accumulated in Hirano bodies, plaque-associated dystrophic neurites and some neurofibrillary tangles (NFTs). SYNJ1 immunoreactivity was higher in neurons and in the senile plaques in AD patients carrying one or two ApolipoproteinE (APOE) ε4 allele(s). In two large cohorts of APOE-genotyped controls and AD patients, SYNJ1 transcripts were significantly increased in AD temporal isocortex compared to control. There was a significant increase in SYNJ1 transcript in APOEε4 carriers compared to non-carriers in AD cohort. SYNJ1 was systematically co-enriched with PHF-tau in the sarkosyl-insoluble fraction of AD brain. In the RIPA-insoluble fraction containing protein aggregates, SYNJ1 proteins were significantly increased and observed as a smear containing full-length and cleaved fragments in AD brains. In vitro cleavage assay showed that SYNJ1 is a substrate of calpain, which is highly activated in AD brains. Our study provides evidence of alterations in SYNJ1 mRNA level and SYNJ1 protein degradation, solubility and localization in AD brains.

中文翻译：

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脂质磷酸酶Synaptojanin 1的表达和溶解性发生重大变化，并与阿尔茨海默氏病的脑部损伤有关。

Synaptojanin 1（SYNJ1）是一种富含脑的脂质磷酸酶，主要参与自噬体/内体运输，突触小泡再循环和磷酸肌醇的代谢。先前的研究表明，SYNJ1多态性对阿尔茨海默氏病（AD）的发病年龄具有重大影响，并且SYNJ1与淀粉样蛋白诱导的毒性有关。然而，在死后人类AD脑组织中SYNJ1蛋白的水平和细胞定位仍然难以捉摸。这项研究旨在检查验尸AD脑中SYNJ1的定位和表达是否发生了改变。我们发现SYNJ1积累在平野体，斑块相关的营养不良性神经突和一些神经原纤维缠结（NFTs）中。携带一或两个载脂蛋白E（APOE）ε4等位基因的AD患者，SYNJ1免疫反应性在神经元和老年斑中较高。与对照组相比，在两个大的APOE基因型对照和AD患者队列中，SYNJ1转录物在AD颞叶皮质中显着增加。与AD队列中的非携带者相比，APOEε4携带者的SYNJ1转录本显着增加。SYNJ1与PHF-tau系统共富集在AD脑的沙克糖基不溶部分中。在含有RIPA的不溶级分中，含有蛋白质聚集体，SYNJ1蛋白显着增加，并在AD脑中观察为含有全长和裂解片段的涂片。体外裂解试验表明，SYNJ1是钙蛋白酶的底物，其在AD脑中被高度激活。我们的研究提供了AD脑中SYNJ1 mRNA水平和SYNJ1蛋白降解，溶解度和定位改变的证据。