A top‐down proteomic approach reveals a salivary protein profile able to classify Parkinson's disease with respect to Alzheimer's disease patients and to healthy controls

Abstract

Parkinson's disease (PD) is a complex neurodegenerative disease with motor and non‐motor symptoms. Diagnosis is complicated by lack of reliable biomarkers. To individuate peptides and/or proteins with diagnostic potential for early diagnosis, severity and discrimination from similar pathologies, the salivary proteome in 36 PD patients was investigated in comparison with 36 healthy controls (HC) and 35 Alzheimer's disease (AD) patients. A top‐down platform based on HPLC‐ESI‐IT‐MS allowed characterizing and quantifying intact peptides, small proteins and their PTMs (overall 51). The three groups showed significantly different protein profiles, PD showed the highest levels of cystatin SA and antileukoproteinase and the lowest of cystatin SN and some statherin proteoforms. HC exhibited the lowest abundance of thymosin β4, short S100A9, cystatin A, and dimeric cystatin B. AD patients showed the highest abundance of α‐defensins and short oxidized S100A9. Moreover, different proteoforms of the same protein, as S‐cysteinylated and S‐glutathionylated cystatin B, showed opposite trends in the two pathological groups. Statherin, cystatins SA and SN classified accurately PD from HC and AD subjects. α‐defensins, histatin 1, oxidized S100A9, and P‐B fragments were the best classifying factors between PD and AD patients. Interestingly statherin and thymosin β4 correlated with defective olfactory functions in PD patients. All these outcomes highlighted implications of specific proteoforms involved in the innate‐immune response and inflammation regulation at oral and systemic level, suggesting a possible panel of molecular and clinical markers suitable to recognize subjects affected by PD.

Salivary Biomarkers for Alzheimer’s Disease: A Systematic Review with Meta-Analysis

“…In a recent study, Contini et al [46] enrolled 36 patients affected by PD, 36 healthy controls, and 35 AD patients (13 in moderate and 22 in mild disease stage). Using a proteomic approach, significant differences between various compounds in diagnostic groups were observed.…”

Salivary Biomarkers for Parkinson’s Disease: A Systematic Review with Meta-Analysis

“…Interestingly, thymosin β4 correlated positively, while statherin 2P negatively, with olfactory function and odor identification. Moreover, α-defensin 3 showed a negative correlation with the Unified Parkinson's Disease Rating Scale (UPDRS III) [59].…”

Protein Oxidative Modifications in Neurodegenerative Diseases: From Advances in Detection and Modelling to Their Use as Disease Biomarkers

“…For instance, excessively nitrated ATP synthase F1 subunit alpha (ATP5F1A) is detected not only in postmortem tissue of AD patients [ 211 ] but also the blood cells of AD patients [ 212 ], suggesting nitrated ATP5F1A as a robust biomarker for AD. Interestingly, it has recently been shown that salivary protein profiling allows to distinguish PD and AD from controls, suggesting that proteins from saliva may be used in the future as another non-invasive and easily accessible source of biomarkers for NDDs diagnosis [ 239 ]; however, whether redox-PTMs would be preserved in salivary samples has yet to be explored. The quantification of redox-PTMs in bodily fluids, such as CSF or blood, remains technically challenging, as discussed in Section 3.2 ; therefore, strict methodological workflows would have to be developed to reduce technical artefacts being introduced [ 240 ].…”