C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.
C-terminal TMEM106B fragments in human brain correlate with disease-associated TMEM106B haplotypes.
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DOI：
10.1093/brain/awad133
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发表时间：
2023-10-03
期刊：
影响因子：
14.5
通讯作者：
Rademakers, Rosa
中科院分区：
文献类型：
--
作者：
Vicente, Cristina;Perneel, Jolien;Wynants, Sarah;Heeman, Bavo;van den Broeck, Marleen;Baker, Matt;Cheung, Simon;Faura, Julia;Mackenzie, Ian R. A.;Rademakers, Rosa
跨膜蛋白 106B (TMEM106B) 是一种严格调控的糖蛋白，主要定位于内体和溶酶体。遗传学研究表明 TMEM106B 单倍型与多种神经退行性疾病的发展有关，其中对具有 TDP-43 病理学的额颞叶变性 (FTLD-TDP) 的影响最强，特别是在颗粒体蛋白前体 (GRN) 突变携带者中。最近，冷冻电子显微镜研究表明，TMEM106B（氨基酸残基 120-254）的 C 末端片段 (CTF) 在 FTLD-TDP 患者的大脑中形成淀粉样原纤维，在患有其他神经退行性疾病的大脑和正常衰老的大脑中也能形成淀粉样原纤维。这些原纤维的功能意义及其与疾病相关 TMEM106B 单倍型的关系仍然未知。我们使用新开发的抗体进行免疫印迹，检测来自不同蛋白质病患者 (n = 64) 以及神经病理学正常个体 (n = 10) 的死后人脑组织中肌糖基不溶部分中的 TMEM106B CTF，并将结果与年龄和 TMEM106B 单倍型相关联。我们进一步将免疫印迹结果与在同一研究人群中进行的免疫组织化学分析进行比较。免疫印迹分析显示，在至少一些接受每种评估条件的个体中，额叶皮质组织的肌氨酰不溶部分中出现了预期的约 30 kDa 条带。大多数患有 GRN 突变的患者显示出代表 TMEM106B CTF 的强烈条带，而在大多数神经系统正常的个体中，该条带不存在或弱得多。在整个队列中，TMEM106B CTF 的存在与年龄（rs = 0.539，P < 0.001）和 TMEM106B 风险单倍型的存在（rs = 0.469，P < 0.001）密切相关。尽管免疫印迹和免疫组化结果之间存在很强的总体相关性（rs = 0.662，P < 0.001），但通过免疫组化发现27例（37%）的TMEM106B CTF含量较高，其中包括大多数神经病理学正常的老年人和携带两种保护性TMEM106B单倍型的个体。我们的研究结果表明，肌氨酰不溶性 TMEM106B CTF 的形成是一种与年龄相关的特征，该特征被 TMEM106B 单倍型修饰，可能是其疾病缓解作用的基础。免疫印迹和免疫组织化学在检测 TMEM106B 病理学方面的差异表明存在多种 TMEM106B CTF，可能具有生物学相关性和疾病影响。维森特等人。报道称，人脑中溶酶体蛋白 TMEM106B 的不溶性 C 末端片段的形成是一种与年龄相关的现象，该现象被 TMEM106B 单倍型修饰，可能是其疾病缓解作用的基础。在风险单倍型携带者中观察到更多的C端片段。
Transmembrane protein 106B (TMEM106B) is a tightly regulated glycoprotein predominantly localized to endosomes and lysosomes. Genetic studies have implicated TMEM106B haplotypes in the development of multiple neurodegenerative diseases with the strongest effect in frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), especially in progranulin (GRN) mutation carriers. Recently, cryo-electron microscopy studies showed that a C-terminal fragment (CTF) of TMEM106B (amino acid residues 120–254) forms amyloid fibrils in the brain of patients with FTLD-TDP, but also in brains with other neurodegenerative conditions and normal ageing brain. The functional implication of these fibrils and their relationship to the disease-associated TMEM106B haplotype remain unknown. We performed immunoblotting using a newly developed antibody to detect TMEM106B CTFs in the sarkosyl-insoluble fraction of post-mortem human brain tissue from patients with different proteinopathies (n = 64) as well as neuropathologically normal individuals (n = 10) and correlated the results with age and TMEM106B haplotype. We further compared the immunoblot results with immunohistochemical analyses performed in the same study population. Immunoblot analysis showed the expected ∼30 kDa band in the sarkosyl-insoluble fraction of frontal cortex tissue in at least some individuals with each of the conditions evaluated. Most patients with GRN mutations showed an intense band representing TMEM106B CTF, whereas in most neurologically normal individuals it was absent or much weaker. In the overall cohort, the presence of TMEM106B CTFs correlated strongly with both age (rs = 0.539, P < 0.001) and the presence of the TMEM106B risk haplotype (rs = 0.469, P < 0.001). Although there was a strong overall correlation between the results of immunoblot and immunohistochemistry (rs = 0.662, P < 0.001), 27 cases (37%) were found to have higher amounts of TMEM106B CTFs detected by immunohistochemistry, including most of the older individuals who were neuropathologically normal and individuals who carried two protective TMEM106B haplotypes. Our findings suggest that the formation of sarkosyl-insoluble TMEM106B CTFs is an age-related feature which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. The discrepancies between immunoblot and immunohistochemistry in detecting TMEM106B pathology suggests the existence of multiple species of TMEM106B CTFs with possible biological relevance and disease implications. Vicente et al. report that the formation of insoluble C-terminal fragments of the lysosomal protein TMEM106B in human brain is an age-related phenomenon which is modified by TMEM106B haplotype, potentially underlying its disease-modifying effect. More C-terminal fragments were observed in risk haplotype carriers.
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