Increase in mitochondrial density within axons and supporting cells in response to demyelination in the Plp1 mouse model

Hogan, V., White, K., Edgar, J. , McGill, A., Karim, S., McLaughlin, M. , Griffiths, I., Turnbull, D. and Nichols, P. (2009) Increase in mitochondrial density within axons and supporting cells in response to demyelination in the Plp1 mouse model. Journal of Neuroscience Research, 87(2), pp. 452-459. (doi:10.1002/jnr.21867)

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Publisher's URL: http://dx.doi.org/10.1002/jnr.21867

Abstract

We used the <i>Plp1</i>-overexpressing transgenic mouse model to investigate whether progressive demyelination of axons results in adaptive changes involving mitochondria within the axons. These models have myelinated axons from birth but gradually lose myelin and develop axonal loss associated with progressive neurological disability analogous to patients with secondary progressive mulltiple sclerosis (SPMS). At 1 and 2 months, electron microscopy demonstrated a significant increase in intraaxonal mitochondrial density in the homozygous line 72 <i>Plp1</i>-overexpressing mice compared with wild type (1.43 ± 0.31 vs. 0.84 ± 0.16 μm<sup>−3</sup>, <i>P</i> = 0.031; 1.66 ± 0.11 vs. 0.92 ± 0.43 μm<sup>−3</sup>, <i>P</i> = 0.02) and a significant increase at 1 and 4 months in the density of mitochondria in the surrounding cells in the same mice (1.86 ± 0.31 vs. 0.81 ± 0.30 μm<sup>−3</sup>, <i>P</i> = 0.006; 2.77 ± 0.44 vs. 1.37 ± 0.42 μm<sup>−3</sup>, <i>P</i> = 0.016). At both 1 and 4 months, COX histochemistry and time-lapse histochemistry demonstrated a significant increase in mitochondrial activity and rate of mitochondrial activity in the homozygous Plp1-overexpressing mouse optic nerve compared with the wild type (112.37 ± 11.9 vs. 136.89 ± 9.1 MeanD, P = 0.006; 128.02 ± 3.0 vs. 188.77 ± 9.7 MeanD P ∠ 0.001; Rate –0.78 ± 0.25 vs. –0.58 ± 0.15 MeanD min−1, P ∠ 0.001; –1.48 ± 0.15 vs. 0.51 ± 0.17 MeanD min−1, <i>P</i> ∠ 0.001, respectively). We propose that adaptive changes involving mitochondria occur within CNS axons in <i>Plp1</i>-overexpressing mice, which may be detrimental to long-term viability. Analogous changes occurring in chronically demyelinated axons in MS lesions would be one mechanism increasing axonal vulnerability in SPMS. © 2008 Wiley-Liss, Inc.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McLaughlin, Dr Mark and Edgar, Dr Julia and Griffiths, Prof Ian and Karim, Ms Saadia
Authors: Hogan, V., White, K., Edgar, J., McGill, A., Karim, S., McLaughlin, M., Griffiths, I., Turnbull, D., and Nichols, P.
Subjects:R Medicine > RC Internal medicine
College/School:College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Journal of Neuroscience Research
Publisher:John Wiley & Sons, Inc.
ISSN:0360-4012
ISSN (Online):1097-4547
Published Online:19 September 2008

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