Transcriptome Sequencing Reveal That Rno-Rsf1_0012 Participates in Levodopa-Induced Dyskinesia in Parkinson's Disease Rats via Binding to Rno-mir-298-5p.

Levodopa-induced dyskinesia (LID) is a common complication of chronic dopamine replacement therapy in the treatment of Parkinson's disease (PD), and a noble cause of disability in advanced PD patients. Circular RNA (circRNA) is a novel type of non-coding RNA with a covalently closed-loop structure, which can regulate gene expression and participate in many biological processes. However, the biological roles of circRNAs in LID are not completely known. In the present study, we established typical LID rat models by unilateral lesions of the medial forebrain bundle and repeated levodopa therapy. High-throughput next-generation sequencing was used to screen circRNAs differentially expressed in the brain of LID and non-LID (NLID) rats, and key circRNAs were selected according to bioinformatics analyses. Regarding fold change ≥2 and p < 0.05 as the cutoff value, there were a total of 99 differential circRNAs, including 39 up-regulated and 60 down-regulated circRNAs between the NLID and LID groups. The expression of rno-Rsf1_0012 was significantly increased in the striatum of LID rats and competitively bound rno-mir-298-5p. The high expression of target genes PCP and TBP in LID rats also supports the conclusion that rno-Rsf1_0012 may be related to the occurrence of LID.

Generation of an induced pluripotent stem cell line, FJMUUHi001-A, from a hereditary Parkinson's disease patient with homozygous mutation of c.189dupA in PARK7.

PARK7 mutations are accountable for the inherited Parkinson's disease. An induced pluripotent stem cell (iPSC) line FJMUUHi001-A was generated by expressing five reprogramming factors, OCT3/4, SOX2, c-MYC, KLF4 and BCL-XL, in peripheral blood mononuclear cells from a 32-year old patient carrying a homozygous mutation of c.189dupA in PARK7. The iPSCs with a normal karyotype had the abilities to differentiate into three germ layers and expressed pluripotency markers without detectable residual plasmids. The cell line FJMUUHi001-A carrying the truncating protein PARK7 could be a useful tool to help comprehend the function of PARK7 in the iPSCs and differentiated cells from them.

Rosmarinic Acid Regulates Microglial M1/M2 Polarization via the PDPK1/Akt/HIF Pathway Under Conditions of Neuroinflammation.

Microglia are resident macrophage-like cells in the central nervous system (CNS). The induction of microglial activation dampens neuroinflammation-related diseases by promoting microglial (re)polarization to the anti-inflammatory (M2) phenotype and can serve as a potential therapeutic approach. Mitochondrial respiration and metabolic reprogramming are required for the anti-inflammatory response of M2 macrophages. However, whether these mitochondrial-dependent pathways are involved in microglial (re)polarization to the anti-inflammatory (M2) phenotype under conditions of lipopolysaccharide (LPS)-induced neuroinflammation remains unclear. Moreover, the mechanisms that coordinate mitochondrial respiration and the functional reprogramming of microglial cells have not been fully elucidated. Rosmarinic acid (RA) possesses antioxidative and anti-inflammatory activities, and we previously reported that RA markedly suppresses LPS-stimulated M1 microglial activation in mice. In this study, we found that RA suppresses M1 microglial polarization and promotes microglial polarization to the M2 phenotype under conditions of neuroinflammation. We identified an increase in mitochondrial respiration and found that metabolic reprogramming is required for the RA-mediated promotion of microglial polarization to the M2 phenotype under LPS-induced neuroinflammation conditions. Hypoxia-inducible factor (HIF) subunits are the key effector molecules responsible for the effects of RA on the restoration of mitochondrial function, metabolic reprogramming, and phenotypic polarization to M2 microglia. The phosphoinositide-dependent protein kinase 1 (PDPK1)/Akt/mTOR pathway is involved in the RA-mediated regulation of HIF expression and increase in M2 marker expression. We propose that the inhibition of PDPK1/Akt/HIFs by RA might be a potential therapeutic approach for inhibiting neuroinflammation through the regulation of microglial M1/M2 polarization. Graphical abstract Schematic of the mechanism through which RA suppresses LPS-induced neuroinflammation by promoting microglial polarization to the M2 phenotype via PDPK1/Akt/HIFs. The bold arrows indicate the direction of the effects of RA (i.e., inhibitory or promoting effects on cytokines or mediators).

Sleep fragmentation as an important clinical characteristic of sleep disorders in Parkinson's disease: a preliminary study.

BACKGROUND: Sleep disorders are one of the earliest non-motor symptoms of Parkinson's disease (PD). Sleep disorders could, therefore, have value for recognition and diagnosis in PD. However, no unified classification and diagnostic criteria exist to evaluate sleep disorders by polysomnography (PSG). Utilizing PSG to monitor sleep processes of patients with PD and analyze sleep disorder characteristics and their relationship with demographic parameters could aid in bridging this gap. This preliminary study aimed to evaluate the clinical characteristic of sleep disorders in PD using PSG. METHODS: PSG was used to evaluate sleep disorders in 27 patients with PD and 20 healthy volunteers between August 2015 and July 2018 in Fujian Medical University Union Hospital. Total sleep time (TST), sleep efficiency (SE), total wake time, and other parameters were compared between the two groups. Finally, the correlation between sleep disorders and age, disease duration, Unified Parkinson's Disease Rating Scale-III scores, Hoehn-Yahr stage, and levodopa dose were analyzed. The main statistical methods included Chi-square test, two independent samples t test, Fisher exact test, and Pearson correlation. RESULTS: Sleep fragmentation in the PD group was significantly increased (74.1%) while difficulty falling asleep and early awakening were not, as compared to healthy controls. No significant differences were found in time in bed, sleep latency (SL), non-rapid eye movement (NREM) stage 1 (N1), N1%, N2, N2%, N3%, and NREM% between PD and control groups; but TST (327.96 ±â€Š105.26 min vs. 414.67 ±â€Š78.31 min, P = 0.003), SE (63.26% ±â€Š14.83% vs. 76.8% ±â€Š11.57%, P = 0.001), R N3 (20.00 [39.00] min vs. 61.50 [48.87] min, P = 0.001), NREM (262.59 ±â€Š91.20 min vs. 337.17 ±â€Š63.47 min, P = 0.003), rapid-eye-movement (REM) (32.50 [33.00] min vs. 85.25 [32.12] min, P < 0.001), REM% (9.56 ±â€Š6.01 vs. 15.50 ±â€Š4.81, P = 0.001), REM sleep latency (157.89 ±â€Š99.04 min vs. 103.47 ±â€Š71.70 min, P = 0.034) were significantly reduced in PD group. CONCLUSION: This preliminary study supported that sleep fragmentation was an important clinical characteristic of sleep disorders in PD. Whether sleep fragmentation is a potential quantifiable marker in PD needs to be further investigated in the future study.

Time-dependent changes in learning ability and induction of long-term potentiation in the lithium-pilocarpine-induced epileptic mouse model.

To explore the mechanism underlying the development of learning deficits in patients with epilepsy, we generated a mouse model for temporal lobe epilepsy by intraperitoneally injecting mice with pilocarpine with lithium chloride, and investigated time-dependent changes in both contextual fear memory of those model mice and long-term potentiation (LTP) in hippocampal CA1 neurons 1 day, 2 weeks, and 6 weeks after the onset of status epilepticus (SE). Fear memory formation did not change 1 day and 2 weeks after the onset of SE, but was significantly reduced after 6 weeks. Induction of LTP was enhanced 1 day after the onset of SE, but returned to the normal level 2 weeks later, and was almost completely attenuated after 6 weeks. The enhancement of LTP was accompanied by an increase in output responses of excitatory postsynaptic potentials, whereas suppression of LTP was accompanied by alteration of the ratio of paired pulse facilitation. These results indicate that time-dependent changes of LTP induction have a causal role in the development of learning deficits of epilepsy patients.