Significant Modifications of the Salivary Proteome Potentially Associated with Complications of Down Syndrome Revealed by Top-down Proteomics

Abstract

People with Down syndrome, a frequent genetic disorder in humans, have increased risk of health problems associated with this condition. One clinical feature of Down syndrome is the increased prevalence and severity of periodontal disease in comparison with the general population. Because saliva plays an important role in maintaining oral health, in the present study the salivary proteome of Down syndrome subjects was investigated to explore modifications with respect to healthy subjects. Whole saliva of 36 Down syndrome subjects, divided in the age groups 10 -17 yr and 18 -50 yr, was analyzed by a top-down proteomic approach, based on the high performance liquid chromatography-electrospray ionization-MS analysis of the intact proteins and peptides, and the qualitative and quantitative profiles were compared with sex-and age-matched control groups. The results showed the following interesting features: 1) as opposed to controls, in Down syndrome subjects the concentration of the major salivary proteins of gland origin did not increase with age; as a consequence concentration of acidic proline rich proteins and S cystatins were found significantly reduced in older Down syndrome subjects with respect to matched controls; 2) levels of the antimicrobial ␣-defensins 1 and 2 and histatins 3 and 5 were significantly increased in whole saliva of older Down syndrome subjects with respect to controls; 3) S100A7, S100A8, and S100A12 levels were significantly increased in whole saliva of Down syndrome subjects in comparison with controls. The increased level of S100A7 and S100A12 may be of particular interest as a biomarker of early onset Alzheimer's disease, which is frequently associated with Down syndrome. Molecular & Cellular Proteomics 12: 10.1074/mcp.M112.026708, 1844 -1852, 2013. Down syndrome (DS)1 is a frequent genetic disorder in humans characterized by premature aging (1). A clinical feature of people with DS is the increased prevalence and severity of periodontal disease compared with age-matched subjects of similar levels of intellectual impairment and compared with the general population (2). Common conditions observed in DS are marginal gingivitis, acute and subacute necrotizing gingivitis, advanced periodontitis, gingival recession, and pocket formation (3, 4). It is known that saliva plays an important role in maintaining oral and dental health, because of the presence of a variety of antimicrobial peptides mainly derived from gland secretion, oral epithelial cells, and neutrophils (5). Several papers reported that neutrophils and T-lymphocyte function is impaired in people with DS (6 -9). However, the salivary secretion of the antimicrobial LL-37 in young individuals with DS was found normal (10). A review of the literature (11, 12) reveals only sporadic and contradictory reports that attempt to explain the role of saliva in the oral health of subjects with DS, and on the whole, information on the biochemical composition of their saliva is scarce. On the basis of the above information, in the present study...

Progress in Top-Down Proteomics and the Analysis of Proteoforms

“…Phosphorylated proteoforms of cardiac troponin I have been identified as candidate biomarkers for chronic heart failure by FTICR-MS (109). Orbitrap-based instrumentation has been applied to intact biomarker studies that have identified candidate proteoform biomarkers in cerebrospinal fluid for pediatric brain tumor prognosis (110) as well as multiple salivary proteoforms potentially associated with complications of Down syndrome, including early onset Alzheimer’s disease (111). Additionally, TDP has been applied to biomarker studies concerning cirrhosis at risk of malignancy (ubiquitin PTMs) (112), schizophrenia and bipolar disorder (113), neurodevelopmental disorders (in combination with MALDI MS imaging) (114), Parkinson’s disease (alpha-synuclein proteoforms) (115), and medulloblastoma and pilocytic astrocytoma (116), all in just the past two years.…”

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A Quantitative Proteomics Approach to Clinical Research with Non-Traditional Samples

“…These results reveal apparent oral modulation of brain function during HIV infection [20]. Quantitative proteomic analysis of saliva has also been considered for the development of less invasive glucose monitoring tools in diabetic patients [21] and Down Syndrome comorbidities biomarker discovery [22]. …”