Extracellular vesicles – upcoming biomarkers in Parkinson's disease's biofluids
DOI: https://doi.org/10.47184/tev.2022.01.06 The search of a biomarker for an early detection of neurodegenerative diseases is one of the biggest challenges of our times. The second most common neurodegenerative disorder Parkinson's disease (PD) is characterized by misfolded alpha-synuclein (a-syn) aggregates within the central nervous system (CNS). Currently, definitive PD diagnosis still requires post-mortem brain examination. As a result, the misdiagnosis of PD based only on clinical symptoms and delayed diagnosis in advanced stages cannot be excluded. Since a-syn aggregates abnormally, it might be an interesting candidate for a biomarker for PD. Lately, extracellular vesicles (EVs) have emerged as potential biomarker in biofluids since accumulating evidence suggests that their content reflects the pathophysiological alterations occurring in their host cells. Interestingly, EVs can cross the blood-brain barrier (BBB) and thus carry information from the CNS to the periphery and vice versa. EVs seem to play a role in other neurodegenerative disorders such as Alzheimer's and prion disease, where they have also shown certain diagnostic potential. For instance, EV isolation protocols have been described to isolate brain-derived EVs from blood samples, increasing their biomarker potential in neurodegenerative disorders. The results published for PD to date are promising: pathology-associated a-syn forms are found in blood-derived EVs, although the underlying mechanisms of formation and release of a-syn-loaded EVs remain unknown. Interestingly, a-syn level correlate with the disease stage, which underlines the importance of neuronal EVs in disease monitoring. Further research extends to other biofluids, like urine, saliva, and cerebrospinal fluid, where EVs can also be found, opening multiple opportunities for more reliable PD diagnosis.
Parkinson’s disease, neuronal extracellular vesicles, blood biomarker, neurodegenerative disorders
Parkinson's Disease
Parkinson´s disease (PD), the second most common neurodegenerative disease, is characterized by progressive degeneration of dopaminergic neurons in the central nervous system (CNS), most prominent within the Substantia nigra pars compacta (SNpC). Neuropathologically, PD is defined by the accumulation of misfolded alpha-synuclein (a-syn) as insoluble "Lewy-Bodies", first described by Dr. Friedrich Lewy in 1912 [1, 2]. a-Syn is expressed mainly at presynaptic terminals, however, to date, its function is not entirely understood. It has been shown to be involved in neurotransmitter release and synaptic interaction via the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) complex. In PD, a-syn forms insoluble aggregates and intracellular occlusions, causing cytotoxic damage by mitochondrial, lysosomal, and proteasomal dysfunction, damaged membranes and altered synaptic functions, subsequently leading to neurodegeneration [3]. The toxicity of misfolded oligomer a-syn was so far shown in vivo and in vitro [4, 5].
In patients, PD manifests with cardinal motor symptoms such as resting tremor, rigidity, bradykinesia, and loss of postural reflexes [6], but patients also often suffer from gastrointestinal (GI) symptoms accompanied by altered gut microbiota composition [7]. Interestingly, a-syn aggregates are also found in the GI tract, and recent findings in the field indicate that this misfolded a-syn may originate from the Enteric Nervous System (ENS) [8]. It was postulated that a-syn pathology might start in the gut reaching the brain via retrograde axonal transport through the vagal nerve (Figure 1).
