Human Molecular Genetics Advance Access originally published online on July 29, 2009
Human Molecular Genetics 2009 18(21):4066-4080; doi:10.1093/hmg/ddp355
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Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease
1 Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, UK 2 Centre for Integrative Physiology, University of Edinburgh Medical School, Edinburgh EH8 9XD, UK 3 Department of Internal Medicine 4 Department of Genetics, Washington University School of Medicine, St Louis, MO, USA 5 Centre for Neural Development and Disease, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
* To whom correspondence should be addressed. Tel: +44 1316503724; Fax: +44 1316504193; Email: t.gillingwater{at}ed.ac.uk
Received June 25, 2009; Accepted July 26, 2009
Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are collectively the most frequent autosomal-recessive neurodegenerative disease of childhood, but the underlying cellular and molecular mechanisms remain unclear. Several lines of evidence have highlighted the important role that non-somatic compartments of neurons (axons and synapses) play in the instigation and progression of NCL pathogenesis. Here, we report a progressive breakdown of axons and synapses in the brains of two different mouse models of NCL: Ppt1–/– model of infantile NCL and Cln6nclf model of variant late-infantile NCL. Synaptic pathology was evident in the thalamus and cortex of these mice, but occurred much earlier within the thalamus. Quantitative comparisons of expression levels for a subset of proteins previously implicated in regulation of axonal and synaptic vulnerability revealed changes in proteins involved with synaptic function/stability and cell-cycle regulation in both strains of NCL mice. Protein expression changes were present at pre/early-symptomatic stages, occurring in advance of morphologically detectable synaptic or axonal pathology and again displayed regional selectivity, occurring first within the thalamus and only later in the cortex. Although significant differences in individual protein expression profiles existed between the two NCL models studied, 2 of the 15 proteins examined (VDAC1 and Pttg1) displayed robust and significant changes at pre/early-symptomatic time-points in both models. Our study demonstrates that synapses and axons are important early pathological targets in the NCLs and has identified two proteins, VDAC1 and Pttg1, with the potential for use as in vivo biomarkers of pre/early-symptomatic axonal and synaptic vulnerability in the NCLs.
The authors wish it to be known that, in their opinion, these authors contributed equally to this study.