Parkinson’s disease biomarkers in human olfactory cleft mucus

点击翻译按钮获取中文摘要

PROJECT SUMMARY Early diagnosis of Parkinson’s disease (PD) remains a big challenge, as clinicians are still lacking reliable biomarkers. PD patients are typically diagnosed when they have already developed motor deficits, indicating significant loss of dopaminergic neurons in the substantia nigra has already occurred. Olfactory impairment is one of the earliest symptoms of PD, often occurring several years before motor deficits. Lewy bodies, the histopathological hallmarks of PD, accumulate in the olfactory bulb in early stages of PD. Recent evidence indicates that aberrant α-synuclein (α-Syn), the main protein component of Lewy bodies, can propagate transneuronally from the olfactory bulb, further suggesting the critical role of the olfactory system in PD pathogenesis. However, to date, human olfactory tissue has not been comprehensively examined to identify molecular biomarkers for PD. The goal of this R21 project is to identify PD biomarkers in human olfactory cleft mucus. Olfactory sensory neurons are concentrated in the superior turbinate of the nose, projecting axons to the olfactory bulb in the brain. Our recent proteomics studies using human olfactory cleft mucus, a biofluid covering the surface of the olfactory mucosa, identified several well-established PD-associated proteins, including α-Syn, DJ-1, and inflammatory biomarkers. Preliminary studies of a PD patient cohort showed that the ratio of α-Syn to DJ-1 and levels of certain inflammatory biomarkers are substantially elevated in the olfactory mucus of PD patients compared to age-matched controls. Preliminary data also showed that the α- Syn/DJ-1 ratio distinguishes PD patients from control subjects with high sensitivity and specificity, showing strong biomarker potential. Here we propose to recruit additional patients with early or advanced PD, as well as age-matched controls. We will use a minimally invasive method established by our research team to collect olfactory cleft mucus. We will conduct immunoassays to determine levels of α-Syn, DJ-1, and multiple inflammatory biomarkers. We will test the hypothesis that the ratio of α-Syn to DJ-1 is a reliable biomarker for PD. Furthermore, we will use machine learning approaches to optimize olfactory biomarkers for PD progression. This multidisciplinary project brings together investigators with expertise in olfaction, PD pathology, inflammation, and machine learning. Our research may have a major impact on patient care by improving early and accurate diagnosis of PD.