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Increase in mitochondrial density within axons and supporting cells in response to demyelination in the Plp1 mouse model
Author(s) -
Hogan Vanessa,
White Kathryn,
Edgar Julia,
McGill Alison,
Karim Saadia,
McLaughlin Mark,
Griffiths Ian,
Turnbull Doug,
Nichols Philip
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21867
Subject(s) - mitochondrion , myelin , genetically modified mouse , medicine , immunohistochemistry , electron microscope , endocrinology , biology , chemistry , pathology , transgene , central nervous system , microbiology and biotechnology , biochemistry , gene , physics , optics
Abstract We used the Plp1 ‐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 Plp1 ‐overexpressing mice compared with wild type (1.43 ± 0.31 vs. 0.84 ± 0.16 μm −3 , P = 0.031; 1.66 ± 0.11 vs. 0.92 ± 0.43 μm −3 , P = 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 −3 , P = 0.006; 2.77 ± 0.44 vs. 1.37 ± 0.42 μm −3 , P = 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 , P < 0.001, respectively). We propose that adaptive changes involving mitochondria occur within CNS axons in Plp1 ‐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.