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ORIGINAL RESEARCH article

Front. Mol. Neurosci.
Sec. Molecular Signalling and Pathways
Volume 17 - 2024 | doi: 10.3389/fnmol.2024.1448215

Proteomics analysis of periplaque and chronic inactive multiple sclerosis lesions

Provisionally accepted
Jordan M. Wilkins Jordan M. Wilkins 1Kiran K. Mangalaparthi Kiran K. Mangalaparthi 2Brian C. Netzel Brian C. Netzel 3*William A. Sherman William A. Sherman 4Yong Guo Yong Guo 1Alicja Kalinowska-Lyszczarz Alicja Kalinowska-Lyszczarz 5*Akhilesh Pandey Akhilesh Pandey 2Claudia F. Lucchinetti Claudia F. Lucchinetti 6*
  • 1 Department of Neurology, Mayo Clinic, Rochester, Minnesota, United States
  • 2 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States
  • 3 Department of Bioinformatics and Computational Biology, University of Minnesota Twin Cities, St. Paul, Minnesota, United States
  • 4 Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, United States
  • 5 Department of Neurology, Poznan University of Medical Sciences, Poznań, Greater Poland, Poland
  • 6 Department of Neurology, The University of Texas at Austin, Austin, Texas, United States

The final, formatted version of the article will be published soon.

    Multiple sclerosis (MS) is a demyelinating disease of the central nervous system characterized by increased inflammation and immune responses, oxidative injury, mitochondrial dysfunction, and iron dyshomeostasis leading to demyelination and axonal damage. In MS, incomplete remyelination results in chronically demyelinated axons and degeneration coinciding with disability. This suggests a failure in the ability to remyelinate in MS, however, the precise underlying mechanisms remain unclear. We aimed to identify proteins whose expression was altered in chronic inactive white matter lesions and periplaque white matter in MS tissue to reveal potential pathophysiological mechanisms. Laser capture microdissection coupled to proteomics was used to interrogate spatially altered changes in formalin-fixed paraffin-embedded brain tissue from three chronic MS individuals and three controls with no apparent neurological complications. Histopathological maps guided the capture of inactive lesions, periplaque white matter, and cortex from chronic MS individuals along with corresponding white matter and cortex from control tissue. Label free quantitation by liquid chromatography tandem mass spectrometry was used to discover differentially expressed proteins between the various brain regions. In addition to confirming loss of several myelin-associated proteins known to be affected in MS, proteomics analysis of chronic inactive MS lesions revealed alterations in myelin assembly, metabolism, and cytoskeletal organization. The top altered proteins in MS inactive lesions compared to control white matter consisted of PPP1R14A, ERMN, SIRT2, CARNS1, and MBLAC2. Our findings highlight proteome changes in chronic inactive MS white matter lesions and periplaque white matter, which may be crucial for proper myelinogenesis, bioenergetics, focal adhesions, and cellular function. This study highlights the importance and feasibility of spatial approaches such as laser capture microdissection-based proteomics analysis of

    Keywords: Differentially expressed proteins, Multiple Sclerosis, Pathology, protein networks, Proteomics, Spatial profiling

    Received: 12 Jun 2024; Accepted: 29 Jul 2024.

    Copyright: © 2024 Wilkins, Mangalaparthi, Netzel, Sherman, Guo, Kalinowska-Lyszczarz, Pandey and Lucchinetti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Brian C. Netzel, Department of Bioinformatics and Computational Biology, University of Minnesota Twin Cities, St. Paul, 55108, Minnesota, United States
    Alicja Kalinowska-Lyszczarz, Department of Neurology, Poznan University of Medical Sciences, Poznań, 61-701, Greater Poland, Poland
    Claudia F. Lucchinetti, Department of Neurology, The University of Texas at Austin, Austin, 78705, Texas, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.