Elevated protein carbonylation, and misfolding in sciatic nerve from db/db and Sod1(-/-) mice: plausible link between oxidative stress and demyelination

• Published in: PloS one 2013-06, Vol.8 (6), p.e65725
• Main Authors: Hamilton, Ryan T, Bhattacharya, Arunabh, Walsh, Michael E, Shi, Yun, Wei, Rochelle, Zhang, Yiqiang, Rodriguez, Karl A, Buffenstein, Rochelle, Chaudhuri, Asish R, Van Remmen, Holly
• Format: Article
• Language: English
• Subjects: Agglomeration; Aging; Animal models; Animals; Apoptosis; Biochemistry; Biology; Carbonyls; Demyelination; Diabetes; Diabetes mellitus; Diabetic neuropathy; Geriatrics; Glucose; In vivo methods and tests; Latency; Lipids; Mice; Muscles; Myelin; Myelin Proteins - chemistry; Myelin Proteins - metabolism; Myelin Sheath - drug effects; Myelin Sheath - physiology; Myelination; Nerve conduction; Nerves; Neural Conduction - drug effects; Oxidation; Oxidative stress; Oxidative Stress - drug effects; Peripheral myelin protein 22; Peripheral neuropathy; Physics; Physiology; Polyneuropathy; Protein Carbonylation - drug effects; Protein folding; Protein Folding - drug effects; Protein Multimerization - drug effects; Protein structure; Protein Structure, Quaternary; Proteins; Rodents; Sciatic nerve; Sciatic Nerve - drug effects; Sciatic Nerve - metabolism; Sciatic Nerve - physiology; Science; Studies; Superoxide dismutase; Superoxide Dismutase - deficiency; Superoxide Dismutase-1; tert-Butylhydroperoxide - pharmacology; Transgenic animals
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0065725

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.