Abstract
Diabetic peripheral polyneuropathy is associated with decrements in motor/sensory neuron myelination, nerve conduction and muscle function; however, the mechanisms of reduced myelination in diabetes are poorly understood. Chronic elevation of oxidative stress may be one of the potential determinants for demyelination as lipids and proteins are important structural constituents of myelin and highly susceptible to oxidation. The goal of the current study was to determine whether there is a link between protein oxidation/misfolding and demyelination. We chose two distinct models to test our hypothesis: 1) the leptin receptor deficient mouse (dbdb) model of diabetic polyneuropathy and 2) superoxide dismutase 1 knockout (Sod1−/−) mouse model of in vivo oxidative stress. Both experimental models displayed a significant decrement in nerve conduction, increase in tail distal motor latency as well as reduced myelin thickness and fiber/axon diameter. Further biochemical studies demonstrated that oxidative stress is likely to be a potential key player in the demyelination process as both models exhibited significant elevation in protein carbonylation and alterations in protein conformation. Since peripheral myelin protein 22 (PMP22) is a key component of myelin sheath and has been found mutated and aggregated in several peripheral neuropathies, we predicted that an increase in carbonylation and aggregation of PMP22 may be associated with demyelination in dbdb mice. Indeed, PMP22 was found to be carbonylated and aggregated in sciatic nerves of dbdb mice. Sequence-driven hydropathy plot analysis and in vitro oxidation-induced aggregation of purified PMP22 protein supported the premise for oxidation-dependent aggregation of PMP22 in dbdb mice. Collectively, these data strongly suggest for the first time that oxidation-mediated protein misfolding and aggregation of key myelin proteins may be linked to demyelination and reduced nerve conduction in peripheral neuropathies.
Highlights
Diabetic peripheral polyneuropathy is a consequence of elevated blood glucose leading to pain and dysfunction of lower extremities and potentially loss of limb
Since demyelination is closely linked to reduced nerve conduction [2] and oxidative stress is associated with reduced sciatic nerve conduction velocity (NCV) and increased tdml as shown in Figure 1A–D, we measured axon diameter, nerve fiber diameter and myelin thickness in 5-mo-old dbm and dbdb mice, and 6 and 20 mo-old Sod12/2 mice in toluidine blue stained sciatic nerve thick sections
These results strongly suggest that oxidative stress is closely associated with alterations in peripheral nerve myelin morphology and function
Summary
Diabetic peripheral polyneuropathy is a consequence of elevated blood glucose leading to pain and dysfunction of lower extremities and potentially loss of limb. The pathologic changes include neuronal/Schwann cell dysfunction, axonal degeneration and chronic motor/sensory neuron demyelination [1]. Reduced nerve conduction velocity (NCV) is observed in diabetic mice [2] and in human type II diabetics [3]. Considerable evidence exists to suggest that oxidative stress may play a critical role in reduction of sciatic nerve conduction and alteration of sciatic/myelin morphology and function in diabetes [4,5,6]; for example, rodent models of type I and II diabetes show increase in oxidative stress and/or damage, e.g. superoxide production, nitrotyrosine and 4-hydroxy nonenal [7,8,9,10]. Myelin membrane is produced by Schwann cells and it is rich in cholesterol, lipid and protein [11]. It is likely that chronic elevation of doi:10.1371/journal.pone.0065725.g001
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