Extracellular Vesicles as Biomarkers for Parkinson’s Disease: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by Jose M. Soriano.

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder, characterized by the misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies and the degeneration of dopaminergic neurons in the substantia nigra pars compacta. The urge for an early diagnosis biomarker comes from the fact that clinical manifestations of PD are estimated to appear once the substantia nigra has deteriorated and there has been a reduction of the dopamine levels from the striatum. Extracellular vesicles (EVs) play an important role in the pathogenesis of neuro-degenerative diseases as PD. 

  • Parkinson’s disease
  • extracellular vesicles
  • exosomes
  • biomarkers

1. α-syn and Its Derivatives

It is widely accepted that the accumulation of misfolded α-syn in PD has a primary role in the pathogenesis of the disease as the main component of Lewy bodies, along with ubiquitinated proteins, that accumulate in the surviving neurons [43][1]. α-syn can be found in the presynaptic terminals of neurons and participates in synaptic plasticity and vesicle trafficking [5,43][1][2]. It can be transferred neuron-to-neuron, with the capacity to form aggregates in the recipient cells but also propagate in a prion-like manner through the system [5][2].
The role of EVs in the carrying of α-syn as a possible pathological way of spreading for PD has been analyzed in 12 of the 29 studies. It was observed by Cerri et al. [14][3], Cao et al. [24][4] and Xia et al. [38][5] that the peripheral exosomal levels of α-syn in PD patients were higher than the levels in HC. EVs α-syn oligomers have garnered interest as the primary neurotoxic form of seeding healthy neurons [30][6].
Mutations in the α-syn-encoding gene SNCA, such as A53T, E46P, A30P, H50Q, G51D and A53E, promote the transformation of α-syn into its most toxic forms, fibrils and oligomers [44][7]. The oligomeric form of α-syn has been identified as the toxic variety participant in PD [30][6] and makes it easier for recipient cells to take up α-syn in this conformation rather than when it is in a free form [45,46][8][9]. In addition, the exosomal environment promotes α-syn aggregation as well, as a way of transportation for its propagation within the CNS and hence for the neurodegenerative process in PD [45,47,48][8][10][11].
Moreover, oligomeric α-syn has also been observed to be promoted by post-translational modifications (PTM) such as phosphorylation, nitration and dopamine (DA) modification. Particularly in PD, phosphorylation at Ser-129 seems to be the most prevalent PTM form of α-syn found in PD with Lewy bodies. It accelerates the formation of α-syn inclusions, as well as neuronal loss in mice [43,49][1][12].

2. PrPc, DJ-1, OxiDJ-1 and Tau Protein

Cellular prion protein (PrPc), a cell-surface glycoprotein highly expressed in central and peripheral nervous system was found increased in plasma exosomes of PD patients vs. HC and associated with cognitive decline [16][13]. These results sustain the role of PrPc in the physiopathological process of PD.
DJ-1 gene encodes DJ-1, a chaperone protein whose main function is to inhibit the aggregation of α-syn. It is also involved in the protection of neurons against oxidative stress and cell death [44][7]. It is worth mentioning that OxiDj-1 can be affected by other clinical pathologies that are undiagnosed at the time of taking the sample. Zhao et al. and Jang et al. demonstrated that plasma neural-derived DJ-1 in exosomes and OxiDJ-1 levels in urine, respectively, were increased in PD patients in comparison to healthy individuals. OxiDJ-1 showed significant differences only when ELISA was performed in comparison with a Western blot assay. Thus, OxiDJ-1 could be studied in larger cohorts as an achievable biomarker for PD detection in a near future [18,40][14][15].
Tau is a well-known protein aggregated in a hyperphosphorylated form in Alzheimer’s disease. EVs can mediate the spread of toxic forms of tau, helping it go from cell-to-cell and into different areas of the brain. Shi et al. pointed out the association between the levels of tau in neuron-derived exosomes in PD patients and the disease progression. Thus, CNS-plasma exosomal tau could be a marker for PD diagnosis [37][16].

3. RNAs and Micro RNAs

LncRNAs, as transcribed RNA molecules, are involved in the regulation of gene expression through epigenetic, translation, transcription and post-transcription mechanisms [52,53][17][18]. On the other hand, micro RNAs (miRNAs) are small noncoding RNA molecules whose length is between 19 to 22 nucleotides and are relevant because of their regulatory role in gene expression through post-transcriptional processes [33][19]. Some examples of dysregulated miRNAs analyzed in this work were miR-1, miR-153, miR-409-3p, miR-19b-3p, miR-10a-5p and let-7g-3p. These were identified as useful screeners to discern PD subjects from healthy controls [20]. So is the case of pure SEVs miR-34a-5p levels that were higher in PD patients even at the beginning stage of PD when the disease duration was less than 5 years [26][21]. Parallel to that are miR-24, miR-195 and miR-19b quantified in serum exosomes, which may be useful noninvasive biomarkers for the diagnosis of PD [31][22]. Caggiu et al. found that miR-155-5p was upregulated, with a significant role in the inflammatory response to α-syn in the CNS [54][23]. Unlike miR-155-5p, miR-146a was downregulated in the PD group, affecting the regulation of the monocyte inflammatory response. miR-125b-5p was found to be downregulated, with a direct impact on the expression of the BDNF-AS molecule, capable of promoting autophagy and apoptosis in MPTP-induced PD [55][24]. It is thought that lncRNAs may influence the expression of target miRNAs, therefore promoting the development of PD [56][25].
LncRNAs and miRNAs have been demonstrated to have implications in the regulation of genes that have been linked to familial PD, which comprises less than 10% of the cases, as follows: (i) Mutations in the SNCA, LRRK2, PARK2 (Parkin), PARK 6 (PINK1) and PARK7 (DJ-1) genes are involved in physiological functions such as kinase signaling, ubiquitin-mediated protein degradation and mitochondrial respiratory chain function [57][26]. (ii) The LRRK2 autosomal dominant mutation has been established as the most common cause of familial PD. Higher levels of exosomal Ser(P)-1292 LRRK2 have been linked to PD and the presence of nonmotor symptoms [19][27].; (iii) R1441C, Y1699C and G20192 LRRK2 mutations increase autophosphorylated LRRK2 protein levels at the Ser-1292 residue [19][27]. (iv) The R1441C mutation appears to promote the formation of abnormally large MVBs which release more exosomes, thus increasing the presence of toxic forms of α-syn in the extracellular space that promote disease spread [9][28]. (v) Ravanidis et al. [58][29] reviewed the literature regarding the dysregulation of several miRNAs in relation with their target proteins and their role in PD, finding evidence of the alterations in miR-205 (LRRK2), miR-7 and mir-153 (SNCA), miR-22 (GBA), mir-544 (DJ-1), among others. (vi) PINK1 participates in different processes regarding mitochondria, such as quality control and damage regulation and has been described as a causative gene in the pathogenesis of PD [52,53][17][18]. (vii) Unlike the mutations mentioned above, the GBA heterozygous mutation was initially linked to PD through clinical observations in populations such as the Ashkenazi Jews [59][30]. GBA transcribes the GCase protein whose main function is the degradation of glucocerebroside into ceramide and glucose, as well as cleaving glucosyl sphingosine. The presence of the GBA1 mutation reduces the enzymatic activity of GCase, which triggers the unfolded protein response and is linked to endoplasmic-reticulum-associated degradation [60][31]. (viii) The combination of GCase activity, plasma L1CAM exosomal Linc-POU3F3 and plasma L1CAM exosomal α-syn has been shown to be more reliable (AUC 0.824) in distinguishing PD vs. controls than each individually [28][32].
The increasing study of RNAs related to PD elucidates their stability characteristics and although numerous factors are involved in their expression profile, they can be correctly quantified by achievable, reproducible methods, leading these to be potential biomarkers for early diagnosis and disease stage [61][33].

4. Neural-Derived Extracellular Vesicles

Neural-derived extracellular vesicles (NDEVs) and their cargo could be the most representative image of the actual state of a neurodegenerative disease such as PD, hence the constant search for specific markers.
EVs are secreted by all types of cells including neurons. NDEVs seem to reflect the brain status in neurodegenerative diseases and also potentially mediate the seeding of pathogenic forms of prone proteins such as α-syn in healthy neurons [62][34].
Numerous researchers have isolated exosomes containing L1CAM from plasma of PD patients to analyze their cargo in order to find a reliable biomarker with a noninvasive sample. From levels of α-syn in plasma neuronal exosomes, tau, LncRNA, GCase activity and DJ-1 are useful for the quantification of neuron-derived exosomes and oligodendrocyte-derived via ELISA, which could help its use as a biomarker for the diagnosis and progression of PD [18,28,32,37,39][14][16][32][35][36]. However, recently Norman et al. evaluated the use of L1CAM for the isolation of NDEV in plasma and CSF and advised against its use as a reliable marker due to its behavior as a soluble protein and not as a specific marker for EVs, explaining its nonspecific binding with soluble proteins such as α-syn [63][37]. In addition, the MISEV 2018 (Minimal Information for Studies of EVs 2018 guidelines) does not propose any biological marker to differentiate subtypes of EVs or to know their cell of origin [7][38].

5. Other Potential Biomarkers

The identification of specific proteins that are involved in PD pathogenesis has brought a new insight in the search for new biomarkers for early PD diagnosis and prognosis. Proteomic technology allows the study of the protein signature of EVs whether in normal conditions or in pathologic scenarios such as PD via different biofluids.
The expression of several proteins in EVs has been studied and analyzed. Jiang et al. found the C1q complex decreased PD patients’ serum exosomes. C1q is the recognition molecule key which contributes to the innate immune defense and regulates the adaptive immune response for the neuroprotection of the CNS and mediation of the formation of central synapses. Although linked to PD, it is still very difficult to elucidate the total role of the expression of C1q in the development of this disease [17,64][39][40].
As mentioned above, proteomics of EV derived from the CNS, erythrocytes or different biofluids have thrown hints for the study of new proteins that are involved in neurological mechanisms.
Lamontagne-Proulx et al. [22][41] performed a proteomic analysis of EVs derived from erythrocytes. In total, 8 out of the 818 proteins identified in the proteome of EVs had expressions that were significantly different in PD patients with various stages. Among these, QDPR is a key catalyzer for the recycling of BH4 (tetrahydrobiopterin), an essential cofactor in the biosynthesis of serotonin and precursors of L-dopa and 5-hydroxy-L-tryptophan (5-HTP) [65][42]. On the other hand, genetic variations in the USP24 protein coding gene, a member of the ubiquitin-specific protease family, is associated with the risk for late-onset PD [66][43].
Gualerzi et al. [23][44] studied the biochemistry of EVs through Raman spectroscopy and found there were biochemical differences between circulating EVs involving proteins, lipids and saccharides, which made it possible to discern between PD patients from HC with an accuracy of 71%. These findings could be useful to evaluate the effectiveness of rehabilitation and pharmacological treatments of PD in the future.
Blood-derived exosomal clusterin, complement C1r subcomponent, afamin, angiotensinogen variant, apolipoprotein D (ApoD), gelsolin and PEDF were progressively upregulated from mild to severe PD [17][39]. It is of major interest to analyze the molecular function of each protein and their interaction with upregulated pathways related to PD disease.
Apolipoprotein A1 (Apo A1), clusterin, complement C1r subcomponent and fibrinogen gamma chain exosomal expression levels in plasma of PD subjects may serve as a biomarker for the diagnosis of PD while Apo A1 could be of use in the future to measure the progression of the disease [27,35][45][46].

6. Neuroinflammation and Neurodegeneration

Neuroinflammation has been recognized as a key mediator in PD progression. There appears to be an alteration in the normal morphology of glial cells, including astrocytes and microglia, as well as an increase in inflammatory mediators in the parenchyma. This glial reaction is thought to happen due to neuronal death or dysfunction [67,68][47][48]. Exosomes containing pathologic forms of α-syn may activate microglia cells, promoting the accumulation and transmission of α-syn, while contributing to neuroinflammation by releasing inflammatory mediators [38][5].
The autophagy–lysosomal pathway (ALP) is capable of degrading aggregated misfolded proteins, such as α-syn, which in pathologic forms cause a neurodegenerative event when taken by microglia [69][49]. The dysfunction of ALP may come from an activation of microglia cells by exosomes containing pathologic forms of α-syn, leading to an accumulation and transmission of this protein into the system [38][5].
In addition to the mechanisms mentioned above, it has been hypothesized that the elevation of phosphorylated Ser-1292 in PD patients with advanced cognitive impairment is related to higher levels of plasma C-reactive protein levels as well as other inflammatory cytokines that eventually exacerbate neurodegeneration [5,14][2][3].

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