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

Hamilton RT, Bhattacharya A, Walsh ME, Shi Y, Wei R, Zhang Y, Rodriguez KA, Buffenstein R, Chaudhuri AR, Van Remmen H - PLoS ONE (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, USA.

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.

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Reduction in peripheral nerve function in dbdb and Sod1−/− mice.Electrophysiologic measurements were performed on dbdb and Sod1−/− mice with their corresponding littermate controls. All measurements of nerve conduction velocity (NCV) and latency were performed under isofluorane anesthesia with skin temperatures between 33°C and 34°C. Sciatic NCV was measured in (A) 5 month old dbdb and (B) 6 month old Sod1−/− mice. Tail distal motor latency was measured in (C) dbdb and (D) Sod1−/− mice. Statistically significant differences obtained from the different groups (n = 15) were tabulated as follows for the mean ± SEM (*p<0.05 by two-tailed t-test).
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pone-0065725-g001: Reduction in peripheral nerve function in dbdb and Sod1−/− mice.Electrophysiologic measurements were performed on dbdb and Sod1−/− mice with their corresponding littermate controls. All measurements of nerve conduction velocity (NCV) and latency were performed under isofluorane anesthesia with skin temperatures between 33°C and 34°C. Sciatic NCV was measured in (A) 5 month old dbdb and (B) 6 month old Sod1−/− mice. Tail distal motor latency was measured in (C) dbdb and (D) Sod1−/− mice. Statistically significant differences obtained from the different groups (n = 15) were tabulated as follows for the mean ± SEM (*p<0.05 by two-tailed t-test).

Mentions: Dbdb mice have been previously shown to have reduced sciatic NCV and increased tail distal motor latency (tdml) [2]. In the current study, we wanted to determine whether oxidative stress is associated with reduced sciatic NCV and increased tdml. We observed a 1.38±0.04 (p<0.001) fold reduction in sciatic NCV by 4 months of age in dbdb mice (Figure 1A). 6-mo-old Sod1−/− mice also demonstrated a 1.36±0.07 (p<0.01) fold reduction in sciatic NCV (Figure 1B). The dbdb mice and Sod1−/− mice exhibited a 1.41±0.04 fold (p<0.001) and 1.12±0.02 fold (p<0.05) increase in tdml, respectively (Figure 1C&D).


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

Hamilton RT, Bhattacharya A, Walsh ME, Shi Y, Wei R, Zhang Y, Rodriguez KA, Buffenstein R, Chaudhuri AR, Van Remmen H - PLoS ONE (2013)

Reduction in peripheral nerve function in dbdb and Sod1−/− mice.Electrophysiologic measurements were performed on dbdb and Sod1−/− mice with their corresponding littermate controls. All measurements of nerve conduction velocity (NCV) and latency were performed under isofluorane anesthesia with skin temperatures between 33°C and 34°C. Sciatic NCV was measured in (A) 5 month old dbdb and (B) 6 month old Sod1−/− mice. Tail distal motor latency was measured in (C) dbdb and (D) Sod1−/− mice. Statistically significant differences obtained from the different groups (n = 15) were tabulated as follows for the mean ± SEM (*p<0.05 by two-tailed t-test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3672154&req=5

pone-0065725-g001: Reduction in peripheral nerve function in dbdb and Sod1−/− mice.Electrophysiologic measurements were performed on dbdb and Sod1−/− mice with their corresponding littermate controls. All measurements of nerve conduction velocity (NCV) and latency were performed under isofluorane anesthesia with skin temperatures between 33°C and 34°C. Sciatic NCV was measured in (A) 5 month old dbdb and (B) 6 month old Sod1−/− mice. Tail distal motor latency was measured in (C) dbdb and (D) Sod1−/− mice. Statistically significant differences obtained from the different groups (n = 15) were tabulated as follows for the mean ± SEM (*p<0.05 by two-tailed t-test).
Mentions: Dbdb mice have been previously shown to have reduced sciatic NCV and increased tail distal motor latency (tdml) [2]. In the current study, we wanted to determine whether oxidative stress is associated with reduced sciatic NCV and increased tdml. We observed a 1.38±0.04 (p<0.001) fold reduction in sciatic NCV by 4 months of age in dbdb mice (Figure 1A). 6-mo-old Sod1−/− mice also demonstrated a 1.36±0.07 (p<0.01) fold reduction in sciatic NCV (Figure 1B). The dbdb mice and Sod1−/− mice exhibited a 1.41±0.04 fold (p<0.001) and 1.12±0.02 fold (p<0.05) increase in tdml, respectively (Figure 1C&D).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas, USA.

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.

Show MeSH
Related in: MedlinePlus