Abstract
Systemic inflammation and mitochondrial dysfunction are involved in neurodegeneration in Parkinson’s disease (PD). Extracellular vesicle (EV) trafficking may link inflammation and mitochondrial dysfunction. In the present study, circulating small EVs (sEVs) from 16 older adults with PD and 12 non-PD controls were purified and characterized. A panel of serum inflammatory biomolecules was measured by multiplex immunoassay. Protein levels of three tetraspanins (CD9, CD63, and CD81) and selected mitochondrial markers (adenosine triphosphate 5A (ATP5A), mitochondrial cytochrome C oxidase subunit I (MTCOI), nicotinamide adenine dinucleotide reduced form (NADH):ubiquinone oxidoreductase subunit B8 (NDUFB8), NADH:ubiquinone oxidoreductase subunit S3 (NDUFS3), succinate dehydrogenase complex iron sulfur subunit B (SDHB), and ubiquinol-cytochrome C reductase core protein 2 (UQCRC2)) were quantified in purified sEVs by immunoblotting. Relative to controls, PD participants showed a greater amount of circulating sEVs. Levels of CD9 and CD63 were lower in the sEV fraction of PD participants, whereas those of CD81 were similar between groups. Lower levels of ATP5A, NDUFS3, and SDHB were detected in sEVs from PD participants. No signal was retrieved for UQCRC2, MTCOI, or NDUFB8 in either participant group. To identify a molecular signature in circulating sEVs in relationship to systemic inflammation, a low level-fused (multi-platform) partial least squares discriminant analysis was applied. The model correctly classified 94.2% ± 6.1% PD participants and 66.7% ± 5.4% controls, and identified seven biomolecules as relevant (CD9, NDUFS3, C-reactive protein, fibroblast growth factor 21, interleukin 9, macrophage inflammatory protein 1β, and tumor necrosis factor alpha). In conclusion, a mitochondrial signature was identified in circulating sEVs from older adults with PD, in association with a specific inflammatory profile. In-depth characterization of sEV trafficking may allow identifying new biomarkers for PD and possible targets for personalized interventions.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting older adults [1]
The lower secretion of mitochondrial-derived vesicles (MDVs) detected in PD participants (Figure 4) may indicate that the mitochondrial quality control (MQC) flux was impaired in PD
This finding is in keeping with previous reports showing an association between PD
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting older adults [1]. PD has shown the fastest growth in prevalence, due to global population aging, greater exposure to environmental risk factors, and longer disease duration [2,3]. Progressive demise of midbrain dopaminergic neurons of the substantia nigra pars compacta and dopamine depletion in the striatum are pathologic hallmarks of PD, which is characterized clinically by motor (i.e., bradykinesia, postural inability, rigidity, and tremor) and non-motor signs and symptoms (e.g., constipation, depression, sleep disorders, cognitive dysfunction) [4]. Dopaminergic neurotoxicity triggered by aggregation of misfolded α-synuclein is a well-established pathologic trait of PD [5]. Age-related mitochondrial dyshomeostasis and the ensuing oxidative stress favor aberrant protein folding and accrual of noxious protein aggregates, including α-synuclein [7]. Whether and how mitochondrial dysfunction and protein dyshomeostasis in neurons are linked to peripheral processes is currently unknown
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