Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss.
Clinically early-stage CSPα mutation carrier exhibits remarkable terminal stage neuronal pathology with minimal evidence of synaptic loss.
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DOI：
10.1186/s40478-015-0256-5
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发表时间：
2015-11-26
影响因子：
7.1
通讯作者：
Sands MS
中科院分区：
文献类型：
--
作者：
Benitez BA;Cairns NJ;Schmidt RE;Morris JC;Norton JB;Cruchaga C;Sands MS
常染色体显性成人型神经元蜡样质脂褐质沉积症（AD-ANCL）是由DNAJC 5基因突变引起的多系统疾病。DNAJC 5编码半胱氨酸串蛋白-α（CSPα），一种假定的突触蛋白。AD-ANCL传统上被认为是一种基于蜡样物质细胞内积累的溶酶体贮积病。在这里，我们首次报告了一个病人在临床早期阶段的疾病，表现出典型的神经元细胞内蜡样物质的积累和初期的神经炎症，但没有迹象表明脑萎缩，神经变性或大量的突触损失的病理结果。有趣的是，我们发现神经元中CSPα或突触素的减少很少或没有明显的减少。相反，晚期AD-ANCL患者的脑匀浆显示SNARE复合物形成突触前蛋白水平显著降低，包括CSPα和SNAP-25显著降低。用于突触蛋白生化分析的冷冻样本对于早期AD-ANLC患者不可用。这些结果表明，本文报告的AD-ANCL患者中观察到的变性可能是细胞索马中CSPα突变的早期影响（最有可能是溶酶体功能）以及随后的神经元丢失和突触功能障碍的结果。
Autosomal dominant adult-onset neuronal ceroid lipofuscinosis (AD-ANCL) is a multisystem disease caused by mutations in the DNAJC5 gene. DNAJC5 encodes Cysteine String Protein-alpha (CSPα), a putative synaptic protein. AD-ANCL has been traditionally considered a lysosomal storage disease based on the intracellular accumulation of ceroid material. Here, we report for the first time the pathological findings of a patient in a clinically early stage of disease, which exhibits the typical neuronal intracellular ceroid accumulation and incipient neuroinflammation but no signs of brain atrophy, neurodegeneration or massive synaptic loss. Interestingly, we found minimal or no apparent reductions in CSPα or synaptophysin in the neuropil. In contrast, brain homogenates from terminal AD-ANCL patients exhibit significant reductions in SNARE-complex forming presynaptic protein levels, including a significant reduction in CSPα and SNAP-25. Frozen samples for the biochemical analyses of synaptic proteins were not available for the early stage AD-ANLC patient. These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPα mutations at the cellular soma, most likely lysosome function, and subsequent neuronal loss and synaptic dysfunction.