Abstract
The progressive loss of dopaminergic neurons in the nigro-striatal system is a major trait of Parkinson’s disease (PD), manifesting clinically as motor and non-motor symptoms. Mitochondrial dysfunction and oxidative stress are alleged pathogenic mechanisms underlying aggregation of misfolded α-synuclein that in turn triggers dopaminergic neurotoxicity. Peripheral processes, including inflammation, may precede and contribute to neurodegeneration. Whether mitochondrial dyshomeostasis in the central nervous system and systemic inflammation are linked to one another in PD is presently unclear. Extracellular vesicles (EVs) are delivery systems through which cells can communicate or unload noxious materials. EV trafficking also participates in mitochondrial quality control (MQC) by generating mitochondrial-derived vesicles to dispose damaged organelles. Disruption of MQC coupled with abnormal EV secretion may play a role in the pathogenesis of PD. Furthermore, due to its bacterial ancestry, circulating mitochondrial DNA can elicit an inflammatory response. Therefore, purification and characterisation of molecules packaged in, and secreted through, small EVs (sEVs)/exosomes in body fluids may provide meaningful insights into the association between mitochondrial dysfunction and systemic inflammation in PD. The EXosomes in PArkiNson Disease (EXPAND) study was designed to characterise the cargo of sEVs/exosomes isolated from the serum of PD patients and to identify candidate biomarkers for PD.
Highlights
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, affecting 2–3% of the population aged 65+
Mitochondrial dysfunction has been associated with several neurodegenerative diseases, including PD, through increased oxidative stress favouring aberrant protein folding and accrual of protein aggregates [5]
Defective mitochondrial quality control (MQC) and loss of mitochondrial DNA homeostasis have emerged as candidate pathogenic mechanisms triggered by oxidative damage in the setting of various age-related conditions [6–8]
Summary
Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, affecting 2–3% of the population aged 65+. PD is characterised by the progressive loss of midbrain dopaminergic neurons of the substantia nigra pars compacta, leading to motor (i.e., bradykinesia, postural inability, rigidity and tremor) and non-motor signs and symptoms (e.g., constipation, depression, sleep, cognitive dysfunction) [1]. Aggregation of misfolded α-synuclein triggering dopaminergic neurotoxicity is a well-established pathologic trait of PD. Mitochondrial dysfunction has been associated with several neurodegenerative diseases, including PD, through increased oxidative stress favouring aberrant protein folding and accrual of protein aggregates (i.e., amyloid β, huntingtin, tau and α-synuclein) [5]. Defective mitochondrial quality control (MQC) and loss of mitochondrial DNA (mtDNA) homeostasis have emerged as candidate pathogenic mechanisms triggered by oxidative damage in the setting of various age-related conditions [6–8]. Chronic inflammation seems to play a role in PD [4]. Whether the two phenomena are inter-related is currently unclear
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