The leptin receptor mutation of the obese Zucker rat causes sciatic nerve demyelination with a centripetal pattern defect

Abstract

Young male Zucker rats with a leptin receptor mutation are obese, have a non-insulin-dependent diabetes mellitus (NIDDM), and other endocrinopathies. Tibial branches of the sciatic nerve reveal a progressive demyelination that progresses out of the Schwann cells (SCs) where electron-contrast deposits are accumulated while the minor lines or intermembranous SC contacts display exaggerated spacings. Cajal bands contain diversely contrasted vesicles adjacent to the abaxonal myelin layer with blemishes; they appear dispatched centripetally out of many narrow electron densities, regularly spaced around the myelin annulus. These anomalies widen and yield into sectors across the stacked myelin layers. Throughout the worse degradations, the adaxonal membrane remains along the axonal neuroplasm. This peripheral neuropathy with irresponsive leptin cannot modulate hypothalamic-pituitaryadrenal axis and SC neurosteroids, thus exacerbates NIDDM condition. Additionally, the ultrastructure of the progressive myelin alterations may have unraveled a peculiar, centripetal mode of trafficking maintenance of the peripheral nervous system myelin, while some adhesive glycoproteins remain between myelin layers, somewhat hindering the axon mutilation. Heading title: Peripheral neuropathy and myelin ARTICLE HISTORY

Peripheral nerve demyelination and a leptin receptor mutation: The obese Zucker rat sciatic nerve demyelination occurs with a centripetal pattern defect

“…Even though, this myelinopathy associates with co-existing endocrinopathies, it demonstrates the SC's metabolic maintenance and turnover of the myelin is important and one has tried to realize, through collection of micrographs, a sort of dynamic, sequential events of the damage throughout the myelin layers. More specifically, in continuity with a previous collection of data [29], this report further illustrates the smallest myelin anomalies of tiny nerve fibers along with other examples of adjacent large size damages found throughout some of the axon's walls. Astonishingly, our ultrastructural findings on demyelination damages could also claim that one may have also unravelled a peculiar centripetal mode of myelin maintenance by SCs in PNS nerves which can be added to another found in CNS, likely originating from nodal zone, that is longitudinal, alongside its membrane's extensions [30][31][32].…”

“…Out of this non-inflammatory PNS demyelination, one can again bring the hypothesis that associated proteins and proteoglycans to the myelin [83], not only can turn over rafts [84][85][86] similarly as in CNS along the Schmidt-Lantermann incisures toward internode membranes [31,32] with a sort of domino effect replacement with renewed adhesive trans membrane components sorting across an already poorly zipped membranes [73]. In our case, wrong accumulations or sorting of myelin components by SCs were also viewed as flawed by insulin disruption [60] including the tiny forming mesaxons as an initial and associated disorder in the architecture alignments of the normal wrapping without being caused by osmotic processing when compared with normal nerves [29,87] and, this throughout along the changed NIDDM myelin, having components with a centripetal insertion, viewed by the evidenced growing blemishes making sorts of trans membranous Ohio University), Rootstown, Ohio, USA have approved the procedures of animal care, anaesthesia, euthanasia, and tissue's collection of this study and concomitant ones [29,[33][34][35]. The collection of tissues of lean and obese Zucker young male rats have been described in detail in a recent publication, with free access [29].…”

“…The few micrographs exemplified here are added to the defects described in previous publications and again reveal that SCs, with their continuous maintenance of the myelin, most of the burden of metabolic changes causing this defective myelin [36][37][38][39][40][41]. The SCs are imposed complex endocrine influences through which expression and sorting of some components of the myelin can be altered [29,35]. Besides the phospholipids that seemed to organize in orderly way layers, the obese Zucker peripheral nerves showed disorders similar to those of the CNS missing a plasmalogen such as the myelin basic protein in the CNS [42].…”

“…In our case, wrong accumulations or sorting of myelin components by SCs were also viewed as flawed by insulin disruption [60] including the tiny forming mesaxons as an initial and associated disorder in the architecture alignments of the normal wrapping without being caused by osmotic processing when compared with normal nerves [29,87] and, this throughout along the changed NIDDM myelin, having components with a centripetal insertion, viewed by the evidenced growing blemishes making sorts of trans membranous Ohio University), Rootstown, Ohio, USA have approved the procedures of animal care, anaesthesia, euthanasia, and tissue's collection of this study and concomitant ones [29,[33][34][35]. The collection of tissues of lean and obese Zucker young male rats have been described in detail in a recent publication, with free access [29]. These obese Zucker rats seemed to be with non-insulin dependent diabetes (NIDDM) which affliction becomes the most common and is increasing rapidly in many populations.…”

“…In the previous publication, comparisons were made between light microscopy (1-µm thick epoxy sections, stained in toluidine blue) to select fields of investigations, and with those in ultrastructure of the myelin covering the nerve fibers of the sciatic tibial nerve branches [29,34]. Here, a small nerve fibre illustrated in Figure 1A of a normal rat is compared with that of an obese, i.e.…”