title: Molecular correlates of axonal and synaptic pathology in mouse models of Batten disease.
abstract: 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 Cln6(nclf) 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.
authors.affiliation: Department of Neuroscience, Centre for the Cellular Basis of Behaviour, Institute of Psychiatry, King's College London, London SE5 9NU, UK.
authors.forename: Catherine
authors.initials: C
authors.lastname: Kielar
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.forename: Alice
authors.initials: A
authors.lastname: Palmer
authors.forename: Sybille
authors.initials: S
authors.lastname: Dihanich
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Wong
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Macauley
authors.forename: Chun-Hung
authors.initials: CH
authors.lastname: Chan
authors.forename: Mark S
authors.initials: MS
authors.lastname: Sands
authors.forename: David A
authors.initials: DA
authors.lastname: Pearce
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cooper
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D015153:Blotting, Western; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism; D009472:Neuronal Ceroid-Lipofuscinoses / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D064249:Securin; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism / Q000473:pathology; D013869:Thiolester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism
chemical_list: C486722:Cln6 protein, mouse; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D064249:Securin; D050825:Synaptosomal-Associated Protein 25; C578002:pituitary tumor-transforming protein 1, human; D050995:Voltage-Dependent Anion Channel 1; D013869:Thiolester Hydrolases; C095299:palmitoyl-protein thioesterase