Limited Proteolysis-Mass Spectrometry Reveals Aging-Associated Changes in Cerebrospinal Fluid Protein Abundances and Structures.

Autor: Shuken SR; Department of Chemistry, Stanford University, Stanford, CA, USA.; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Rutledge J; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA., Iram T; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Losada PM; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA., Wilson EN; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA., Andreasson KI; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.; Program in Immunology, Stanford University, Stanford, CA, USA., Leib RD; Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University, Stanford, CA, USA., Wyss-Coray T; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.; Wu Tsai Neurosciences Institute, Stanford University, Stanford, CA, USA.; Paul F. Glenn Center for the Biology of Aging, Stanford University School of Medicine, Stanford, California, USA.
Jazyk: angličtina
Zdroj: Nature aging [Nat Aging] 2022 May; Vol. 2 (5), pp. 379-388. Date of Electronic Publication: 2022 Apr 11.
DOI: 10.1038/s43587-022-00196-x
Abstrakt: 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-PLA 2 , 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.
Competing Interests: Competing Interests The authors declare no competing interests.
Databáze: MEDLINE
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