METTL14 Regulates the m6A Modification of TRAF6 to Suppress Mitochondrial Dysfunction and Ferroptosis in Dopaminergic Neurons via the cGAS-STING Pathway.

OBJECTIVES: The degeneration of dopaminergic (DA) neurons has emerged as a crucial pathological characteristic in Parkinson's disease (PD). To enrich the related knowledge, we aimed to explore the impact of the METTL14-TRAF6-cGASSTING axis in mitochondrial dysfunction and ferroptosis underlying DA neuron degeneration. METHODS: 1-methyl-4-phenylpyridinium ion (MPP+) was used to treat DA neuron MN9D to develop the PD cell models. Afterward, a cell counting kit, flow cytometer, DCFH-DA fluorescent probe, and Dipyrromethene Boron Difluoride staining were utilized to measure the cell viability, iron concentration, ROS level, and lipid peroxidation, respectively. Meanwhile, the mitochondrial ultrastructure, the activity of mitochondrial respiratory chain complexes, and levels of malondialdehyde and glutathione were monitored. In addition, reverse transcription-quantitative polymerase chain reaction and western blot assays were adopted to measure the expression of related genes. cGAS ubiquitylation and TRAF6 messenger RNA (mRNA) N6-methyladenosine (m6A) levels, the linkages among METTL14, TRAF6, and the cGAS-STING pathway were also evaluated. RESULTS: METTL14 expression was low, and TRAF6 expression was high after MPP+ treatment. In MPP+-treated MN9D cells, METTL14 overexpression reduced ferroptosis, ROS generation, mitochondrial injury, and oxidative stress (OS) and enhanced mitochondrial membrane potentials. TRAF6 overexpression had promoting impacts on mitochondrial dysfunction and ferroptosis in MPP+-treated MN9D cells, which was reversed by further overexpression of METTL14. Mechanistically, METTL14 facilitated the m6A methylation of TRAF6 mRNA to down-regulate TRAF6 expression, thus inactivating the cGAS-STING pathway. CONCLUSION: METTL14 down-regulated TRAF6 expression through TRAF6 m6A methylation to inactivate the cGAS-STING pathway, thereby relieving mitochondrial dysfunction and ferroptosis in DA neurons.

Vinpocetine and coenzyme Q10 combination alleviates cognitive impairment caused by ionizing radiation by improving mitophagy.

OBJECTIVE: This research was designed to ascertain the effect and mechanism of vinpocetine (VIN) and coenzyme Q10 (CoQ10) combination on cognitive impairment induced by ionizing radiation (IR). METHODS: Cognitive impairment in mice was induced by 9-Gy IR, and they were intraperitoneally injected with VIN, CoQ10, or VIN + CoQ10. Then novel object recognition and Morris water maze tests were used to detect cognitive function. The number of hippocampal neurons and BrdU+Dcx+ cells was observed by Nissl and immunofluorescence staining. Mitochondrial respiratory complex I, adenosine triphosphate (ATP), and mitochondrial membrane potential (MMP) were evaluated, as well as oxidative stress injury. Mitophagy in hippocampal neurons was evaluated by observing the ultrastructure of hippocampal neurons and assessing the expression of mitophagy-related proteins. RESULTS: IR reduced novel object discrimination index, the time for platform crossing, and the time spent in platform quadrant, in addition to neuron loss, downregulated levels of mitochondrial respiratory complex I, ATP, and MMP, aggravated oxidative stress injury, increased expression of LC3 II/I, Beclin1, PINK1, and parkin, and decreased P62 expression. VIN or CoQ10 treatment mitigated cognitive dysfunction, neurons loss, mitochondrial damage, and oxidative stress injury, and enhanced mitophagy in hippocampal neurons. VIN and CoQ10 combination further protected against IR-induced cognitive dysfunction than VIN or CoQ10 alone. CONCLUSION: VIN combined with CoQ10 improved neuron damage, promoted mitophagy, and ameliorated cognitive impairment in IR mice.

Potential of nobiletin against Alzheimer's disease through inhibiting neuroinflammation.

OBJECTIVE: This study aimed to explore the mechanism of Nobiletin attenuating Alzheimer's disease (AD) by inhibiting neuroinflammation. METHODS: The expression of inflammatory cytokines and HMGB-1 in serum of AD patients were examined. Microglia (MGs) were treated with different doses of Nobiletin before LPS and Nigericin induction. Cell viability and apoptosis were determined by CCK-8 and TUNEL assays, respectively. APP/PS1 mice were gavaged with Nobiletin, and Morris water maze (MWM) was established to record swimming speed, escape latency, the number of platform crossings, and time spent in the platform quadrant. MGs activation in brain tissues was evaluated by immunofluorescence. The expression of pyroptosis-related proteins, inflammatory cytokines, and HMGB-1 was determined in the hippocampus and MGs. RESULTS: The levels of inflammatory cytokines and HMGB-1 were high in serum of AD patients. Treatment with different concentrations of Nobiletin prominently enhanced cell viability and reduced apoptosis and the expression of inflammatory cytokine and pyroptosis-related proteins in LPS + Nigericin-induced MGs. Gavage of different doses of Nobiletin into APP/PS1 mice shortened the escape latency in mice, diminished MGs activation in brain tissues, and remarkably elevated the number of platform crossings and the time spent in the platform quadrant without obvious change in swimming speed, suggesting that Nobiletin improved the spatial learning and memory abilities in APP/PS1 mice. The expression of pyroptosis-related proteins, HMGB-1, and inflammatory cytokines was decreased dramatically by Nobiletin in the hippocampus of APP/PS1 mice. CONCLUSIONS: Nobiletin can inhibit neuroinflammation by inhibiting HMGB-1, pyroptosis-related proteins, and inflammatory cytokines, thus mitigating AD.

Is awake physiological confirmation necessary for DBS treatment of Parkinson's disease today? A comparison of intraoperative imaging, physiology, and physiology imaging-guided DBS in the past decade.

BACKGROUND: Deep brain stimulation (DBS) is a well-established surgical therapy for Parkinson's disease (PD). Intraoperative imaging (IMG), intraoperative physiology (PHY) and their combination (COMB) are the three mainstream DBS guidance methods. OBJECTIVE: To comprehensively compare the use of IMG-DBS, PHY-DBS and COMB-DBS in treating PD. METHODS: PubMed, Embase, the Cochrane Library and OpenGrey were searched to identify PD-DBS studies reporting guidance techniques published between January 1, 2010, and May 1, 2018. We quantitatively compared the therapeutic effects, surgical time, target error and complication risk and qualitatively compared the patient experience, cost and technical prospects. A meta-regression analysis was also performed. This study is registered with PROSPERO, number CRD42018105995. RESULTS: Fifty-nine cohorts were included in the main analysis. The three groups were equivalent in therapeutic effects and infection risks. IMG-DBS (p < 0.001) and COMB-DBS (p < 0.001) had a smaller target error than PHY-DBS. IMG-DBS had a shorter surgical time (p < 0.001 and p = 0.008, respectively) and a lower intracerebral hemorrhage (ICH) risk (p = 0.013 and p = 0.004, respectively) than PHY- and COMB-DBS. The use of intraoperative imaging and microelectrode recording correlated with a higher surgical accuracy (p = 0.018) and a higher risk of ICH (p = 0.049). CONCLUSIONS: The comparison of COMB-DBS and PHY-DBS showed intraoperative imaging's superiority (higher surgical accuracy), while the comparison of COMB-DBS and IMG-DBS showed physiological confirmation's inferiority (longer surgical time and higher ICH risk). Combined with previous evidence, the use of intraoperative neuroimaging techniques should become a future trend.

Persistent adverse effects following different targets and periods after bilateral deep brain stimulation in patients with Parkinson's disease.

BACKGROUND: Performed as one of the major treatments for advanced Parkinson's disease (PD), deep brain stimulation (DBS) surgery can induce adverse effects (AEs) on cognition, gait, mood, speech and swallowing, which are frequently reported and seriously affect the patient's daily life. OBJECTIVE: To comprehensively analysis the adverse effect rates (AERs) of cognition, mood, gait, speech and swallowing after bilateral DBS in patients with PD. METHOD: We performed a systematic search in PubMed, EMBASE and the Cochrane Library to collect all the articles reporting AEs after DBS in sufferers of PD. The cited articles were also manually searched. RESULTS: A total of 31 articles were quantitatively analyzed. Random-effects models were used to calculate the AERs and 95% confidence intervals. Of all patients, the pooled AER of the five types of events was 24.0%. Specifically, the risks of cognition, mood and speech disturbance were higher after subthalamic nucleus (STN) -DBS than after globus pallidus interna (GPi) -DBS: 25.1% versus 14.6%, 26.3% versus 22.2% and 29.0% versus 19.6%, respectively. However, the AER of dysphagia was slightly lower after STN-DBS: 8.6% versus 10.1%. The risk of gait disorders was similar between two target groups in sub-analysis of random control trials (RCTs): 38.3% in STN group and 37.3% in GPi group. In three follow-up intervals, short-term follow-up (STF), mid-term follow-up (MTF) and long-term follow-up (LTF), gait (17.6%~19.9%~28.0%), speech (7.8%~26.9%~31.5%) and mood (7.4%~24.9%~30.7%) disorders worsened progressively. While cognitive disturbance (22.5%~27.1%~16.7%) reached its highest rate at MTF. CONCLUSION: STN-DBS was 10% more likely to cause cognitive and speech disturbance than GPi-DBS, while STN-DBS had a lower risk of dysphagia. Two target groups had similar effects on gait. The pooled AER increased over time, while cognitive disturbance reached its highest rate at the 6- to 18-month follow-up. Additionally, speech and mood disturbance deteriorated rapidly from STF to MTF. Further investigation of the pathophysiology will help alleviate those AEs after DBS.