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Axonal damage in the making: Neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter

Petzold, A; Tozer, DJ; Schmierer, K; (2011) Axonal damage in the making: Neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter. Experimental Neurology , 232 (2) pp. 234-239. 10.1016/j.expneurol.2011.09.011. Green open access

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Abstract

Aims: Multiple sclerosis (MS) leaves a signature on the phosphorylation and thus proton binding capacity of axonal neurofilament (Nf) proteins. The proton binding capacity in a tissue is the major determinant for exchange between bound and free protons and thus the magnetisation transfer ratio (MTR). This study investigated whether the MTR of non-lesional white matter (NLWM) was related to the brain tissue concentration of neurofilament phosphoforms. Methods: Unfixed post-mortem brain slices of 12 MS patients were analysed using MTR, T1 at 1.5 T. Blocks containing NLWM were processed for embedding in paraffin and inspected microscopically. Adjacent tissue was microdissected, homogenised and specific protein levels were quantified by ELISA for the Nf heavy chain (NfH) phosphoforms, glial fibrillary acidic protein (GFAP), S100B and ferritin. Results: Averaged hyperphosphorylated NfH (SMI34) but not phosphorylated NfH (SMI35) levels were different between individual patients NLWM. The concentration of hyperphosphorylated NfH-SMI34 correlated with T1 (R = 0.70, p = 0.0114) and — inversely — with MTR (R =−0.73, p = 0.0065). NfH-SMI35 was not correlated to any of the MR indices. Conclusions: Post-translational modifications of axonal proteins such as phosphorylation of neurofilaments occur in NLWM and may precede demyelination. The resulting change of proton mobility influences MTR and T1. This permits the in vivo detection of these subtle tissue changes on a proteomic level in patients with MS.

Type: Article
Title: Axonal damage in the making: Neurofilament phosphorylation, proton mobility and magnetisation transfer in multiple sclerosis normal appearing white matter
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.expneurol.2011.09.011
Publisher version: https://doi.org/10.1016/j.expneurol.2011.09.011
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
URI: https://discovery.ucl.ac.uk/id/eprint/10089435
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