Adler Gabrielle L, Kiernan Matthew C, Tan Rachel H
School of Medical Sciences (Neuroscience), Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australia.
Brain and Mind Centre, University of Sydney, Sydney, NSW, Australia.
Ann Neurol. 2025 Jun 20. doi: 10.1002/ana.27300.
Biomarkers of disease pathogenesis are critically needed for amyotrophic lateral sclerosis (ALS) to facilitate diagnosis and patient stratification into appropriate therapeutic trials. Proteomic studies offer significant potential to advance this, but reproducibility across laboratories is a key component toward identifying protein changes that can be translated into clinical applications.
A combined analysis of 25 proteomic studies in human ALS biospecimens was performed to identify proteins consistently altered in ALS postmortem tissue, cerebrospinal fluid, or blood, as well as across primary regions of ALS pathology and peripheral biofluids. We consolidated these datasets into a user-friendly database "FindMND Biomarker," which is an accessible search tool that allows users to quickly determine how often, and in which biospecimen types, their proteins of interest are dysregulated in patients with ALS.
Our combined analysis identified 1,458 altered proteins in ALS, and revealed consistent dysregulation in mitochondrial, cytoplasmic, and RNA binding proteins in primary and later affected regions of ALS pathology. Remarkable consistency in the direction and dysregulation of chitinases and gelsolin proteins were observed across ALS biofluids. Comparisons of postmortem tissue and biofluids reinforce several known protein changes, and highlighted novel proteins of interest that may drive disease pathogenesis.
The biospecimen type in which protein dysregulation is most consistently identified provides important insight into disease, and whether these represent potential measures of disease pathogenesis or systemic changes. By streamlining proteins by reproducibility and biospecimen type, FindMNDBiomarker is a useful resource that provides new mechanistic insights, and facilitates the prioritization of ALS-associated proteins for further validation and investigation. ANN NEUROL 2025.
肌萎缩侧索硬化症（ALS）迫切需要疾病发病机制的生物标志物，以促进诊断并将患者分层纳入适当的治疗试验。蛋白质组学研究在推进这方面具有巨大潜力，但不同实验室之间的可重复性是识别可转化为临床应用的蛋白质变化的关键要素。
对25项关于人类ALS生物样本的蛋白质组学研究进行了综合分析，以确定在ALS死后组织、脑脊液或血液中，以及在ALS病理的主要区域和外周生物流体中持续发生改变的蛋白质。我们将这些数据集整合到一个用户友好的数据库“FindMND生物标志物”中，这是一个可访问的搜索工具，允许用户快速确定他们感兴趣的蛋白质在ALS患者中失调的频率以及在哪些生物样本类型中失调。
我们的综合分析在ALS中鉴定出1458种改变的蛋白质，并揭示了在ALS病理的主要和后期受影响区域中线粒体、细胞质和RNA结合蛋白存在一致的失调。在ALS生物流体中观察到几丁质酶和凝溶胶蛋白在失调方向上具有显著的一致性。死后组织和生物流体的比较强化了一些已知的蛋白质变化，并突出了可能驱动疾病发病机制的新的感兴趣蛋白质。
最一致地鉴定出蛋白质失调的生物样本类型为疾病提供了重要见解，以及这些是否代表疾病发病机制的潜在指标或全身变化。通过按可重复性和生物样本类型精简蛋白质，FindMNDBiomarker是一个有用的资源，它提供了新的机制见解，并有助于对ALS相关蛋白质进行优先排序，以便进一步验证和研究。《神经病学纪事》2025年。
