Abstract
The elderly population will significantly increase in the next decade and, with it, the proportion of people affected by age-related diseases. Among them, one of the most invalidating is Parkinson’s disease (PD), characterized by motor- and non-motor dysfunctions which strongly impair the quality of life of affected individuals. PD is characterized by the progressive degeneration of dopaminergic neurons, with consequent dopamine depletion, and the accumulation of misfolded α-synuclein aggregates. Although 150 years have passed since PD first description, no effective therapies are currently available, but only palliative treatments. Importantly, PD is often diagnosed when the neuronal loss is elevated, making difficult any therapeutic intervention. In this context, two key challenges remain unanswered: (i) the early diagnosis to avoid the insurgence of irreversible symptoms; and (ii) the reliable monitoring of therapy efficacy. Research strives to identify novel biomarkers for PD diagnosis, prognosis, and therapeutic follow-up. One of the most promising sources of biomarkers is represented by extracellular vesicles (EVs), a heterogeneous population of nanoparticles, released by all cells in the microenvironment. Brain-derived EVs are able to cross the blood-brain barrier, protecting their payload from enzymatic degradation, and are easily recovered from biofluids. Interestingly, EV content is strongly influenced by the specific pathophysiological status of the donor cell. In this manuscript, the role of EVs as source of novel PD biomarkers is discussed, providing all recent findings concerning relevant proteins and miRNAs carried by PD patient-derived EVs, from several biological specimens. Moreover, the contribution of mitochondria-derived EVs will be dissected. Finally, the promising possibility to use EVs as source of markers to monitor PD therapy efficacy will be also examined. In the future, larger cohort studies will help to validate these EV-associated candidates, that might be effectively used as non-invasive and robust source of biomarkers for PD.
Highlights
1.1 Parkinson’s disease: an aging related disorderAging is a universal but not uniform process, characterized by multiple and complex mechanisms [1]
In this work we present an up-to-date collection of potential extracellular vesicles (EVs)-based biomarkers, which include the most important Parkinson’s disease (PD)-linked proteins and miRNAs
Kitamura and colleagues in 2018 isolated EVs from plasma samples of PD patients, as well as from healthy subjects. They demonstrated that the levels of Apolipoprotein A1 (APO A1), Apolipoprotein J (APO J) and Complement C1r, which prevent protein aggregation in physiological conditions, decreased in PD patients compared with healthy controls (HC) [144]
Summary
Aging is a universal but not uniform process, characterized by multiple and complex mechanisms (e.g., genomic instability, epigenetic alterations, telomere shortening, deregulated nutrient sensing, mitochondrial dysfunction, stem cell exhaustion, alteration in intercellular signaling etc.) [1]. The resulting inflammatory microenvironment is associated with oxidative stress mediators, such as reactive oxygen (ROS) and nitrogen species (RNS), that in turn amplify microglial activation with detrimental effects for mitochondrial homeostasis, leading to increased DAergic neuron vulnerability, and/or neuronal death [52,53,54,55,56,57] Both aging and inflammation dramatically impact on DAergic neuron vulnerability, as well as on the capacity for neurorepair in PD, as a result of a vicious crosstalk between genetic and environmental factors. Investigations aimed at identifying preclinical PD biomarkers represent an important step towards the development of more efficacious neuroprotective therapies This would delay the onset and progression of the disease – limiting the ongoing degeneration process before the appearance of the first clinical symptoms – and help to unravel novel etiopathogenetic mechanisms/targets for PD. The possibility to identify early signs of the disease investigating pre-clinical biomarkers, in particular within EVs, is summarized
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