UCL Huntington's Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
PLoS One. 2020 Aug 17;15(8):e0233820. doi: 10.1371/journal.pone.0233820. eCollection 2020.
Molecular markers derived from cerebrospinal fluid (CSF) represent an accessible means of exploring the pathobiology of Huntington's disease (HD) in vivo. The endo-lysosomal/autophagy system is dysfunctional in HD, potentially contributing to disease pathogenesis and representing a potential target for therapeutic intervention. Several endo-lysosomal proteins have shown promise as biomarkers in other neurodegenerative diseases; however, they have yet to be fully explored in HD. We performed parallel reaction monitoring mass spectrometry analysis (PRM-MS) of multiple endo-lysosomal proteins in the CSF of 60 HD mutation carriers and 20 healthy controls. Using generalised linear models controlling for age and CAG, none of the 18 proteins measured displayed significant differences in concentration between HD patients and controls. This was affirmed by principal component analysis, in which no significant difference across disease stage was found in any of the three components representing lysosomal hydrolases, binding/transfer proteins and innate immune system/peripheral proteins. However, several proteins were associated with measures of disease severity and cognition: most notably amyloid precursor protein, which displayed strong correlations with composite Unified Huntington's Disease Rating Scale, UHDRS Total Functional Capacity, UHDRS Total Motor Score, Symbol Digit Modalities Test and Stroop Word Reading. We conclude that although endo-lysosomal proteins are unlikely to have value as disease state CSF biomarkers for Huntington's disease, several proteins demonstrate associations with clinical severity, thus warranting further, targeted exploration and validation in larger, longitudinal samples.
源自脑脊液（CSF）的分子标志物代表了一种探索亨廷顿病（HD）体内病理生物学的可行方法。内溶酶体/自噬系统在 HD 中功能失调，可能导致疾病发病机制，并代表潜在的治疗干预靶点。几种内溶酶体蛋白在其他神经退行性疾病中作为生物标志物显示出前景；然而，它们在 HD 中尚未得到充分探索。我们对 60 名 HD 突变携带者和 20 名健康对照者的 CSF 中的多个内溶酶体蛋白进行了平行反应监测质谱分析（PRM-MS）。使用控制年龄和 CAG 的广义线性模型，所测量的 18 种蛋白质中没有一种在浓度上显示出 HD 患者与对照组之间的显着差异。这通过主成分分析得到了证实，在代表溶酶体水解酶、结合/转运蛋白和固有免疫系统/外周蛋白的三个成分中，没有发现任何一个成分在疾病阶段有显着差异。然而，有几种蛋白质与疾病严重程度和认知测量有关：最显着的是淀粉样前体蛋白，它与综合统一亨廷顿病评定量表、UHDRS 总功能能力、UHDRS 总运动评分、符号数字模态测试和 Stroop 单词阅读有很强的相关性。我们得出的结论是，尽管内溶酶体蛋白不太可能作为亨廷顿病的疾病状态 CSF 生物标志物具有价值，但有几种蛋白质与临床严重程度相关，因此需要在更大的纵向样本中进一步进行有针对性的探索和验证。
