Abstract
Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by olfactory dysfunction in the early stages. α-Synuclein pathologies in the olfactory organs are shown to spread to the brain through the nose-brain axis. We first developed a nasal epithelial PD cellular model by treating RPMI-2650 cells with α-synuclein preformed fibrils (PFF). Upon uptake of PFF, RPMI-2650 cells showed mitochondrial proteome alteration and downregulation of parkin, which has previously been identified as a nasal biomarker of PD. Functional cluster analysis of differentially expressed genes in RPMI-2650 cells revealed various pathways affected by α-synuclein pathology, including the detection of chemical stimulus involved in sensory perception, olfactory receptor activity, and sensory perception of smell. Among genes that were most affected, we validated, by real-time quantitative PCR, the downregulation of MAP3K8, OR10A4, GRM2, OR51B6, and OR9A2, as well as upregulation of IFIT1B, EPN1, OR1D5, LCN, and OTOL1 in PFF-treated RPMI-2650 cells. Subsequent analyses of clinical samples showed a downregulation of OR10A4 and OR9A2 transcripts and an upregulation of IFIT1B in cells isolated from the nasal fluid of PD patients, as compared to those from the controls (cutoff value = 0.5689 for OR9A2, with 72.4% sensitivity and 75% specificity, and 1.4658 for IFIT1B, with 81.8% sensitivity and 77.8% specificity). Expression levels of these nasal PD markers were not altered in nasal fluid cells from SWEDD (scans without evidence of dopaminergic deficits) patients with PD-like motor symptoms. These nasal markers were significantly altered in patients of PD with hyposmia compared to the control hyposmic subjects. Our results validated the α-synuclein-treated nasal epithelial cell model to identify novel biomarkers for PD and suggest the utility of olfactory transcripts, along with olfactory dysfunction, in the diagnosis of PD.
Highlights
Parkinson’s disease (PD) is pathologically characterized by Lewy body inclusions, mainly composed of phosphorylated and misfolded α-synuclein aggregates [1,2]
There was no alteration in the expression of pyruvate dehydrogenase and cytochrome c oxidase subunit 4 (COX IV) (Figure 1F,G). These results indicate that the preformed fibrils (PFF) treatment affects gene expression profiles and mitochondrial proteome in RPMI-2650 cells, thereby suggesting its utility for screening potential nasal PD biomarkers derived from nasal epithelial cells
Since α-synuclein aggregates are found in the body fluids of PD patients and olfactory dysfunction appears in most PD patients in the early stages, we considered that α-synuclein may impact the nasal environment
Summary
Parkinson’s disease (PD) is pathologically characterized by Lewy body inclusions, mainly composed of phosphorylated and misfolded α-synuclein aggregates [1,2]. Lewy body pathologies propagate to different brain regions in PD patients, correlating with the progressive manifestation of nonmotor and motor clinical symptoms [3]. Olfactory dysfunction develops at relatively early stages of PD, many years before the canonical motor symptoms appear. Postmortem olfactory bulb tissues from several patients of PD have shown atrophic changes and the presence of α-synuclein pathologies [4,5,6]. An injection of preformed fibrils (PFF) of α-synuclein into the olfactory bulb led to olfactory dysfunction and the subsequent propagation of Lewy-like pathology into different regions of the brain in mice [7]. To convert a diagnosis of clinical olfactory dysfunction into the specific diagnosis of PD, additional molecular biomarkers specific to PD are required
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