Can the Fact That Myelin Proteins Are Old and Break down Explain the Origin of Multiple Sclerosis in Some People?

Abstract

Recent discoveries may change the way that multiple sclerosis (MS) is viewed, particularly with regard to the reasons for the untoward immune response. The fact that myelin proteins are long-lived, and that by the time we are adults, they are extensively degraded, alters our perspective on the reasons for the onset of autoimmunity and the origin of MS. For example, myelin basic protein (MBP) from every human brain past the age of 20 years, is so greatly modified, that it is effectively a different protein from the one that was laid down in childhood. Since only a subset of people with such degraded MBP develop MS, a focus on understanding the mechanism of immune responses to central nervous system (CNS) antigens and cerebral immune tolerance appear to be worthwhile avenues to explore. In accord with this, it will be productive to examine why all people, whose brains contain large quantities of a "foreign antigen", do not develop MS. Importantly for the potential causation of MS, MBP from MS patients breaks down differently from the MBP in aged controls. If the novel structures formed in these MS-specific regions are particularly antigenic, it could help explain the origin of MS. If verified, these findings could provide an avenue for the rational synthesis of drugs to prevent and treat MS.

Keywords: age-related; isoaspartate; myelin basic protein; posttranslational modification; protein decomposition; proteomics.

Figure 1

When old proteins in the body degrade, novel structures are formed. l-Asp and l-Asn residues can spontaneously convert over time to 4 isomeric forms, via a cyclic intermediate as illustrated. An uncharged Asn becomes a mixture of four negatively charged Asp residues. Probably of greatest impact as potential immune inducers are l-isoAsp and d-isoAsp. In the case of d-isoAsp the α-carbon is racemised and the polypeptide chain is also extended by the insertion of a CH₂ group, as highlighted by the red bonds. In adult MBP, many positively charged Arg residues have been converted to neutral citrulline residues. Together these abundant post translational modifications (PTMs) lead to protein unfolding and the generation of novel antigens.

Figure 2

Myelin basic protein is highly modified in the adult human brain. Histogram showing the relative abundances of some of the major sites of modification in MBP from the cerebellum in controls and patients with MS. Three main types of modifications were observed: deimination of Arg (to form citrulline), racemisation and isomerisation of Asp, and deamidation of Asn and Gln. It should be noted that each site of Asn/Gln deamidation contains four Asp/Glu isomers due to the process of spontaneous racemisation and isomerisation (see Figure 1). The average ages of the two groups were controls 46 ± 22 years (n = 10) and MS patients 60 ± 12 years (n = 8). Shown are mean values ± SD. Detailed subject data from Friedrich et al., 2016 [9].

Figure 3

MBP in MS patients is different from MBP in controls. Highlighted in red (Arg) and blue (Asp) are 5 amino acid residues that differ significantly within a 19 amino acid sequence. This cluster includes Arg 31, Asp 34, Arg 43, Asp 48, and Arg 49. For each site, the degree of change is greater in the MS patients; the only exception being Arg 31. Statistical data are shown in Figure 2 and are summarised from Friedrich et al. [9]. The model of MBP was generated using I-Tasser [25] and PyMOL Molecular Graphics System was used to render the 3D structure.

Figure 4

A simplified scheme illustrating how modified MBP in the brain could lead to the induction of MS. One mechanism that could underpin the onset of MS is illustrated. MBP in the human CNS is heavily modified by age 18, with some modification sites being MS-specific. Modified MBP and/or peptides derived from it by autolysis [14,35], or possibly protease action, diffuse via the lymphatic system to the CSF. Subsequent drainage via the lymphatic vessels to the deep cervical lymph node may permit priming of T cell responses. Once primed, T and B cells become self-reactive. In ways analogous to those described for EAE, these self-reactive species cause damage to the myelin and inflammation of the CNS, which manifests as MS (see text for details). APC, Antigen-presenting cell.

Figure 5

MBP is more highly racemized in females. Racemisation of aspartic acid + asparagine (Asx) in the MBP of age-matched male () and female () subjects. Elevated levels of d-Asx were found in females by comparison to males (p = 0.029, Mann–Whitney U test). Male n = 4, female n = 4, age range 51–87 years. Mean ± SEM.