Proteomics of Multiple Sclerosis: Inherent Issues in Defining the Pathoetiology and Identifying (Early) Biomarkers

Abstract

Multiple Sclerosis (MS) is a demyelinating disease of the human central nervous system having an unconfirmed pathoetiology. Although animal models are used to mimic the pathology and clinical symptoms, no single model successfully replicates the full complexity of MS from its initial clinical identification through disease progression. Most importantly, a lack of preclinical biomarkers is hampering the earliest possible diagnosis and treatment. Notably, the development of rationally targeted therapeutics enabling pre-emptive treatment to halt the disease is also delayed without such biomarkers. Using literature mining and bioinformatic analyses, this review assessed the available proteomic studies of MS patients and animal models to discern (1) whether the models effectively mimic MS; and (2) whether reasonable biomarker candidates have been identified. The implication and necessity of assessing proteoforms and the critical importance of this to identifying rational biomarkers are discussed. Moreover, the challenges of using different proteomic analytical approaches and biological samples are also addressed.

Early Changes in Exo- and Endocytosis in the EAE Mouse Model of Multiple Sclerosis Correlate with Decreased Synaptic Ribbon Size and Reduced Ribbon-Associated Vesicle Pools in Rod Photoreceptor Synapses

“…IF data confirmed lower levels of phospho-dynamin1 in photoreceptor synapses of MOG/CFA-injected EAE retinas in comparison to the respective controls ( Figure 12 and Figure 13 ). Interestingly, proteome analyses identified down-regulation of proteins involved in endocytosis in the mouse EAE model [ 121 , 122 ].…”

The roles of microglia and astrocytes in phagocytosis and myelination: Insights from the cuprizone model of multiple sclerosis

“…How these heterogeneities in gene expression and biochemical processes temporally align with morphological changes remains unclear. Moreover, while these technological advancements reveal the multifactorial characteristics of microglia and astrocytes, it is not clear how many of these genes are translated to functional proteins, nor specifically which proteoforms (Sen et al, 2021) are involved, since no parallel studies were found using transcriptomic or any (top‐down) proteomic analyses. Do microglia and astrocytes show differential transcriptional/proteome profiles in different animal models of MS?…”

“…Animal models are the backbone of MS research, not only for long‐standing efforts to define the pathoetiology of the disease, but also for the development of therapeutics, despite the fact that no single animal model fully reflects the complex heterogeneity of MS (Ransohoff, 2012; Sen et al, 2021; Sen et al, 2020b; Stys et al, 2012). Of the commonly used animal models such as experimental autoimmune encephalomyelitis (EAE), CPZ, ethidium bromide, lysolecithin, LPS, diphtheria toxin (DPT), and Theiler's murine encephalomyelitis virus (Denic et al, 2011; Procaccini et al, 2015; Ransohoff, 2012; Sen et al, 2019b; Sousa et al, 2018; Traka et al, 2010), CPZ is mostly used to study de‐ and remyelination.…”

Proteomes Are of Proteoforms: Embracing the Complexity

“…These are but a few examples deserving of more robust consideration rather than continuing to do things ‘because that is how they have always been done and others do it similarly as well’. If the latter common rationale were actually true—that is, things are not in fact done identically between labs, even apparently using the same protocol and instrumentation—there would not exist the current level of inter-lab variation and irreproducibility of findings [ 255 ]. The real issue seems to be whether the field seeks to continue its now almost blind commitment to the speed of analyses or whether quality, depth, and quantification in proteoform analysis become recognized as the critical objectives, as will be absolutely necessary with respect to proteome complexity.…”