Paranodal reorganization results in the depletion of transverse bands in the aged central nervous system

Abstract

Paranodal axo-glial junctional complexes anchor the myelin sheath to the axon and breakdown of these complexes presumably facilitates demyelination. Myelin deterioration is also prominent in the aging central nervous system (CNS); however, the stability of the paranodal complexes in the aged CNS has not been examined. Here, we show that transverse bands, prominent components of paranodal junctions, are significantly reduced in the aged CNS; however, the number of paired clusters of both myelin and axonal paranodal proteins is not altered. Ultrastructural analyses also reveal that thicker myelin sheaths display a “piling” of paranodal loops, the cytoplasm-containing sacs that demarcate the paranode. Loops involved in piling are observed throughout the paranode and are not limited to loops positioned in either the nodal- or juxtanodal-most regions. Here, we propose that as myelination continues, previously anchored loops lose their transverse bands and recede away from the axolemma. Newly juxtaposed loops then lose their transverse bands, move laterally to fill in the gap left by the receded loops and finally reform their transverse bands. This paranodal reorganization results in conservation of paranodal length, which may be important in maintaining ion channel spacing and axonal function. Furthermore, we propose that transverse band reformation is less efficient in the aged CNS, resulting in the significant reduction of these junctional components. Although demyelination was not observed, we propose that loss of transverse bands facilitates myelin degeneration and may predispose the aged CNS to a poorer prognosis following a secondary insult.

Fibroblast Growth Factor Receptor Signaling in Oligodendrocytes Regulates Myelin Sheath Thickness

“…Morphometric quantification of myelin thickness by g-ratio analysis (ratio of axon diameter to myelinated fiber diameter, expressed as scatter plots) confirmed a relative reduction of myelin thickness in the mutants (Figure 1D) at all ages examined, from P30 to 10 months. Indeed, consistent with previous studies (Blakemore 1974; Peters et al, 2001; Shepherd et al, 2012), when average g-ratios were plotted as a function of age (Figure 1 E), the myelin thickness in the spinal cords of normal mice continued to increase (with decreasing g-ratos) up to at least 10 months of age. In contrast, the double mutants remained "arrested" in development, with the same g-ratios that had been reached after two weeks.…”

Paranodal permeability in “myelin mutants”

“…Thus, the number of paranodal loops contacting the axolemma to form paranodal junctions does not increase in proportion to the total number of myelin lamellae. Hence, the relation between paranode length and axon diameter is highly non-linear, especially in the case of large-caliber PNS fibers (Berthold and Rydmark, 1983; Bertram and Schroder, 1993; Shepherd et al, 2010). …”

Nfasc155H and MAG are Specifically Susceptible to Detergent Extraction in the Absence of the Myelin Sphingolipid Sulfatide

“…Two sets of criteria were used to identify pairs of neurofascin-containing paranodes as previously described [34]. Briefly, all paired rectangular clusters (corresponding to two adjacent paranodes) separated by a small region void of labeling (corresponding to the node of Ranvier) were identified as a single paranodal pair.…”