神经退行性变
蛋白质水解
脑脊液
免疫印迹
蛋白质组
蛋白质组学
生物
化学
生物化学
病理
神经科学
医学
疾病
酶
基因
作者
Steven R. Shuken,Jarod Rutledge,Tal Iram,Patricia Morán Losada,Edward N. Wilson,Katrin I. Andreasson,Ryan D. Leib,Tony Wyss‐Coray
出处
期刊:Nature Aging
日期:2022-04-11
卷期号:2 (5): 379-388
被引量:18
标识
DOI:10.1038/s43587-022-00196-x
摘要
Cerebrospinal fluid (CSF) proteins and their structures have been implicated repeatedly in aging and neurodegenerative diseases. Limited proteolysis-mass spectrometry (LiP-MS) is a method that enables proteome-wide screening for changes in both protein abundance and structure. To screen for novel aging-associated changes in the CSF proteome, we performed LiP-MS on CSF from young and old mice with a modified analysis pipeline. We found 38 protein groups change in abundance with aging, most dominantly immunoglobulins of the IgM subclass. We discovered six high-confidence candidates that appeared to change in structure with aging, of which Kng1, Itih2, Lp-PLA2, and 14-3-3 proteins have binding partners or proteoforms known previously to change in the brain with Alzheimer's disease. Intriguingly, using orthogonal validation by Western blot we found the LiP-MS hit Cd5l forms a covalent complex with IgM in mouse and human CSF whose abundance increases with aging. SOMAmer probe signals for all six LiP-MS hits in human CSF, especially 14-3-3 proteins, significantly associate with several clinical features relevant to cognitive function and neurodegeneration. Together, our findings show that LiP-MS can uncover age-related structural changes in CSF with relevance to neurodegeneration.
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