PDF(Pubmed)
Abstract：
Wasteosomes (or corpora amylacea) are polyglucosan bodies that appear in the human brain with aging and in some neurodegenerative diseases, and have been suggested to have a potential role in a nervous system cleaning mechanism. Despite previous studies in several neurodegenerative disorders, their status in frontotemporal lobar degeneration (FTLD) remains unexplored. Our study aims to characterize wasteosomes in the three primary FTLD proteinopathies, assessing frequency, distribution, protein detection, and association with aging or disease duration. Wasteosome scores were obtained in various brain regions from 124 post-mortem diagnosed sporadic FTLD patients, including 75 participants with tau (FTLD-tau), 42 with TAR DNA-binding protein 43 (FTLD-TDP), and 7 with Fused in Sarcoma (FTLD-FUS) proteinopathies, along with 29 control subjects. The wasteosome amount in each brain region for the different FLTD patients was assessed with a permutation test with age at death and sex as covariables, and multiple regressions explored associations with age at death and disease duration. Double immunofluorescence studies examined altered proteins linked to FTLD in wasteosomes. FTLD patients showed a higher accumulation of wasteosomes than control subjects, especially those with FTLD-FUS. Unlike FTLD-TDP and control subjects, wasteosome accumulation did not increase with age in FTLD-tau and FTLD-FUS. Cases with shorter disease duration in FTLD-tau and FTLD-FUS seemed to exhibit higher wasteosome quantities, whereas FTLD-TDP appeared to show an increase with disease progression. Immunofluorescence studies revealed the presence of tau and phosphorylated-TDP-43 in the periphery of isolated wasteosomes in some patients with FTLD-tau and FTLD-TDP, respectively. Central inclusions of FUS were observed in a higher number of wasteosomes in FTLD-FUS patients. These findings suggest a role of wasteosomes in FTLD, especially in the more aggressive forms of FLTD-FUS. Detecting these proteins, particularly FUS, in wasteosomes from cerebrospinal fluid could be a potential biomarker for FTLD.
摘要：
Wasteosomes（或淀粉体）是随着衰老和某些神经退行性疾病而出现在人脑中的聚葡聚糖体，并被认为在神经系统清洁机制中具有潜在作用。尽管以前在几种神经退行性疾病中进行了研究，他们在额颞叶变性（FTLD）中的地位仍未被探索。我们的研究旨在表征三种主要FTLD蛋白病中的废物体，评估频率，分布，蛋白质检测，与衰老或疾病持续时间有关。在死后诊断为散发性FTLD的124例患者的各个大脑区域中获得了废物体评分，包括75名tau参与者（FTLD-tau），42与TARDNA结合蛋白43（FTLD-TDP），和7融合肉瘤（FTLD-FUS）蛋白病，以及29个对照对象。不同FLTD患者的每个大脑区域的废物量通过以死亡年龄和性别为协变量的置换检验进行评估。多元回归分析了与死亡年龄和疾病持续时间的关系.双重免疫荧光研究检查了废物体中与FTLD相关的改变的蛋白质。FTLD患者的废物堆积量高于对照组，尤其是那些有FTLD-FUS的。与FTLD-TDP和对照受试者不同，FTLD-tau和FTLD-FUS的废物体积累不随年龄增长而增加。FTLD-tau和FTLD-FUS疾病持续时间较短的病例似乎表现出更高的废物数量，而FTLD-TDP似乎随着疾病进展而增加。免疫荧光研究显示，在一些FTLD-tau和FTLD-TDP患者中，分离的废体周围存在tau和磷酸化的TDP-43，分别。在FTLD-FUS患者中，在较高数量的废物体中观察到FUS的中央包裹体。这些发现表明废物在FTLD中的作用，特别是在更具侵略性的FLTD-FUS形式中。检测这些蛋白质，尤其是FUS,来自脑脊液的废物可能是FTLD的潜在生物标志物。
