title: Temporal lobe proteins implicated in synaptic failure exhibit differential expression and deamidation in vascular dementia.
abstract: Progressive synaptic failure precedes the loss of neurons and decline in cognitive function in neurodegenerative disorders, but the specific proteins and posttranslational modifications that promote synaptic failure in vascular dementia (VaD) remain largely unknown. We therefore used an isobaric tag for relative and absolute proteomic quantitation (iTRAQ) to profile the synapse-associated proteome of post-mortem human cortex from vascular dementia patients and age-matched controls. Brain tissue from VaD patients exhibited significant down-regulation of critical synaptic proteins including clathrin (0.29; p < 1.0⋅10(-3)) and GDI1 (0.51; p = 3.0⋅10(-3)), whereas SNAP25 (1.6; p = 5.5⋅10(-3)), bassoon (1.4; p = 1.3⋅10(-3)), excitatory amino acid transporter 2 (2.6; p = 9.2⋅10(-3)) and Ca(2+)/calmodulin dependent kinase II (1.6; p = 3.0⋅10(-2)) were substantially up-regulated. Our analyses further revealed divergent patterns of protein modification in the dementia patient samples, including a specific deamidation of synapsin1 predicted to compromise protein structure. Our results reveal potential molecular targets for intervention in synaptic failure and prevention of cognitive decline in VaD.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Xavier
authors.initials: X
authors.lastname: Gallart-Palau
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Aida
authors.initials: A
authors.lastname: Serra
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Jingru
authors.initials: J
authors.lastname: Qian
authors.affiliation: Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Memory, Aging and Cognition Centre, National University Health System, Singapore.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Chen
authors.affiliation: Institute for Ageing and Health, NIHR Biomedical Research Building, Newcastle University, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, United Kingdom.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore. Electronic address: sksze@ntu.edu.sg.
authors.forename: Siu Kwan
authors.initials: SK
authors.lastname: Sze
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D015140:Dementia, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D017433:Protein Structure, Secondary; D040901:Proteomics / Q000379:methods*; D013569:Synapses / Q000378:metabolism* / Q000473:pathology; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology
chemical_list: D009419:Nerve Tissue Proteins
keywords: Clathrin; Deamidation; Synapsin1; Synaptic failure; Vascular dementia; α/β-tubulins