Although there has been a significant progress to understand the mechanisms which lead to PD, it is still challenging to determine specific biomarkers enabling accurate diagnose of the disease, classification and risk factors and predict probable patients [33]. Accumulation of a large number of pathological features α-synuclein, Lewy bodies and other proteins resulted from abnormal proteasome function, mitochondrial dysfunction, oxidative stress, calcium homeostasis, synaptic transmission and neuroinflammation has been shown in multiple studies [4, 5, 15, 34, 35]. The combined action of these mechanisms causes autophagy and apoptosis of dopaminergic neurons in the SNpc, promoting the development of PD [12, 36]. There has been accumulating significant evidence of the important role of lncRNAs in these activities of PD pathogenesis [6, 12, 15]. It is generally perceived that diagnosis and treatment of the disease will be facilitated by detecting lncRNAs’ profiles that extracted from serum, plasma, CSF, saliva and tissue samples [24]. In this study, we studied to determine the levels of four of these lncRNAs H19, GAS5, HAR1B and LINC01783 in the sera of PD patients.
The ubiquitin-proteasome system (UPS), a nonlysosomal pathway of protein degradation, removes damaged mutant and aberrant proteins in cells, regulates cell cycle DNA damage and repairs apoptosis. UPS dysfunction causes abnormal accumulation of protein within the cell and gets an important role in the pathogenesis of PD [12, 37]. Reduced mitochondrial activity promotes free radical formation and enhances the susceptibility of tissues to oxidative stress, resulting in damage to cellular DNA, lipids and proteins. It has been shown that PD patients have high oxidative stress in the brain, meanwhile dopaminergic neurons don’t have the ability to control oxidative stress. The process of apoptosis is highly related to mitochondrial dysfunction and oxidative stress, so plays an important role in death of the dopaminergic neurons in the disease [38]. Autophagy-mediated-protein degradation is a process in which the proteins are engulfed within vesicles that fuse with the lysosomes to degrade proteins. Enhanced autophagy can effectively counter PD [12]. Neuroinflammation is so important in PD. The inflammatory cytokines, affecting the integrity of the blood-brain barrier and synaptic plasticity, accelerate the aging and degeneration of dopaminergic neurons [12]. To clarify the pathogenesis of PD and discover new therapeutic targets, it is clearly important to elucidate lncRNA-mediated regulation of the α-synuclein that linked to some mechanisms such as abnormal modification of α-synuclein after translation, aggregation of α-synuclein, toxic effects and degradation [39]. During the inhibition of α-synuclein toxicity by the traditional Chinese medicine Acanthopanax senticosus (AS), a commonly used agent, 341 lncRNAs were differentiated under the stimulation of α-synuclein in microarray expression analysis. 29 of these lncRNAs were involved in the inhibition of α-synuclein neurotoxicity mechanism mediated by AS and 19 were potentially related to α-synuclein neurotoxicity [40]. The potential mechanisms of lncRNAs include the inhibition of PD-linked genes' expressions, the reduction in production of α-synuclein, the maintenance of autophagy system balance, the delay in the apoptosis of dopaminergic neurons, the alleviation of nerve inflammation and so forth. All these findings indicate that lncRNAs have the potential to become a biomarker and therapeutic target for PD.
Soreq et al in 2014, for the first time, utilized a whole-transcriptome RNA sequencing to determine all the transcripts that code proteins in leukocyte and lncRNAs in PD patients and controls. However, they couldn’t fully elucidate the detailed functions of the identified lncRNAs. 13 lncRNAs showed differentiated expression levels and selective PD-induced alteration. These researchers also found 4 of these lncRNAs were reversed after deep brain stimulation treatment. Comparisons of the peripheral blood and brain tissue samples of the PD patients and healthy individuals reveal common differences in lncRNAs, with the same expression trends. In this study it was stated that U1 levels (ENST00000415386 which is LINC01738) were differentiated in PD patients’ amygdala and leukocytes [8].
A recent study found that PD-related genes associated with lncRNAs decreased in the SN and cerebellum of patients, just as consistent with the results obtained in peripheral blood cells [41]. lncRNAs in the CSF of patients with PD have a higher frequency compared with controls, corroborating previous reports that various lncRNAs performed essential functions in the regulation of PD progression [42]. Both animal and cell models are commonly used in PD researches. Abnormal expression of approximately 756 lncRNAs was detected in the SNpc of the presymptomatic mice. Although these studies cannot exactly replicate the pathological changes in human PD patients, 87 of lncRNAs had significant differentiations in the expression in the SN of PD patients, when compared to the normal tissues [43].
Kraus and colleagues studied lncRNA expression levels in brain tissue of postmortem 20 PD patients and 10 healthy controls [10]. It was identified that GAS5 and HAR1B were so abundant and expressed in brain samples and so, they were used as normalizers. They found that only 5 patients had significant alterations when compared to controls, out of 90 non-coding transcripts investigated in the study. lncRNA H19 upstream conserved regions 1 and 2 were downregulated significantly [10]. Besides, it was shown in recent studies lncRNA H19 can play protective roles against dopaminergic neuronal loss and apoptosis in mice models with PD [13, 17]. lncRNA H19 regulates the p53/Notch1 pathway to inhibit neurogenesis in ischemic stroke [44]. H19 is one of the first lncRNAs, linked to different types of cancer, such as bladder cancer, colorectal cancer, and hepatocellular carcinoma [45]. Moreover, lncRNA H19 regulates neuronal apoptosis in AD, suggesting that the regulation of lncRNA networks have unneglectable influence on AD pathology, that is they may lighten the unclear etiology of AD and lead current drug therapy which is unsatisfactory [46].
GAS5, as a member of the lncRNA family, is located on chromosome 1 of the human genome. Studies have shown that GAS5 is abnormally expressed in many tumor disorders and plays an oncogene role by inhibiting apoptosis. Moreover, GAS5 also takes place in the development of inflammation-related disorders [16]. There have been some studies investigating its role in neurological disorders such as ischemic stroke and AD. Acetylcholine release has a related role in the cholinergic nervous system of AD patients [47]. Microglia-induced neuroinflammation plays a significant role in PD pathogenesis. In another study, it has been shown that GAS5 can activate microglia and increase the expression level of inflammatory cytokines [48]. All these findings highly suggest GAS5 involvement in PD development, but further studies are still needed for GAS5 role in PD.
As being confirmed, lncRNAs are expressed in many regions of the brain [9]. The study demonstrated that HAR1 specifically expressed in Cajal-Retzius neurons in the development human neocortex during a period of 7 to 19 gestational weeks, a crucial time for cortical neuron specification and migration [21]. It upregulates reelin. lncRNA LINC01783 (Gene ID: 100132147) (ENST00000415386) locates in the 1p36.13 region of human genome. Underlying its importance in cancer, in a recent study it was reported that LINC01783 had an association with the proliferation, migration, and invasion of cervical cancer cells [25].
No significant difference was shown when the expression levels of four candidate lncRNAs, H19, GAS5, HAR1B and LINC01783 in the sera of PD patients were studied in comparison to those of healthy controls. However, it was found that there was solely a significant negative correlation between GAS5 and HY stage and UPDRS II, III and total scores when the relationship between the expressed levels of these four lncRNAs were examined in age, gender, duration of education, disease duration, disease onset finding, HY stage, UPDRS scores and treatment doses. Even though this parameter was suggested to have a role in inflammation in other previous studies, in our study we revealed that it was associated with the clinical severity of the disease and there was no correlation with other lncRNAs’ levels. Other studies did not report any significant relationship in the literature [10, 13, 15, 16]. It was found that LINC01783 lncRNA was significantly higher only in PD patients with positive family history.
In conclusion, as we know this is the first clinical study in order to explore the expression levels of serum lncRNAs in Turkish PD patients. It may help to understand PD pathogenesis better and more in detail to search serum lncRNAs levels, but there have been few studies in the literature so far. It can suggest important contribution to the development of potential biomarkers for PD and also the identification of new therapeutic targets, although the mechanisms by which lncRNAs role in complex physiological and pathological cases such as PD have not been elucidated fully yet.