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Microglial activation-induced neuroinflammation is closely associated with the development of Parkinson disease (PD). Macroautophagy/autophagy regulates many biological processes, but the role of autophagy in microglial activation during PD development remains largely unclear. In this study, we showed that deletion of microglial Atg5 caused PD-like symptoms in mice, characterized by impairment in motor coordination and cognitive learning, loss of tyrosine hydroxylase (TH) neurons, enhancement of neuroinflammation and reduction in dopamine levels in the striatum. Mechanistically, we found that inhibition of autophagy led to NLRP3 (NLR family pyrin domain containing 3) inflammasome activation via PDE10A (phosphodiesterase 10A)–cyclic adenosine monophosphate (cAMP) signaling in microglia, and the sequential upregulation of downstream IL1B/IL-1β in turn increased the expression of MIF (macrophage migration inhibitory factor [glycosylation-inhibiting factor]), a pro-inflammatory cytokine. Inhibition of NLRP3 inflammasome activation by administration of MCC950, a specific inhibitor for NLRP3, decreased MIF expression and neuroinflammatory levels, and rescued the loss of TH neurons in the substantial nigra (SN). Interestingly, we found that serum MIF levels in PD patients were significantly elevated. Taken together, our results reveal an important role of autophagy in microglial activation-driven PD-like symptoms, thus providing potential targets for the clinical treatment of PD. Abbreviations: ATG: autophagy related; cAMP: cyclic adenosine monophosphate; cKO: conditional knockout; NOS2/INOS: nitric oxide synthase 2, inducible; IL1B: interleukin 1 beta; ITGAM/CD-11b: integrin alpha M/cluster of differentiation molecule 11B; MAP1LC3: microtubule-associated protein 1 light chain 3; MIF: macrophage migration inhibitory factor (glycosylation-inhibiting factor); NLRP3: NLR family pyrin domain containing 3; PBS: phosphate-buffered saline; PD: parkinson disease; PDE10A: phosphodiesterase 10A; SN: substantial nigra; TH: tyrosine hydroxylase; TNF: tumor necrosis factor; WT: wild type. [ABSTRACT FROM AUTHOR]

J Neurol Neurosurg Psychiatry. J Neurol. 2018; 265: 2633 - 45. J Neurol Neurosurg Psychiatry. [Extracted from the article]

Background: Recent evidence suggested that several single nucleotide polymorphisms (SNPs) of inflammation-related genes (TNF-a rs1799964, IL-1a rs1800587, IL-1b rs16944, IL-8 rs4073, ICAM-1 rs5498) were associated with multiple system atrophy (MSA). Herein, we conducted this casecontrol study to evaluate the possible correlation between the five SNPs related to inflammation and MSA in Chinese Han population. Methods and Patients: We recruited 154 sporadic patients with MSA and 223 health controls in this study. All subjects were genotyped for the five SNPs using polymerase chain reaction amplification and Sanger sequencing. Results: TNF-a rs1799964, genotype distribution and minor allele frequency (MAF) showed significant differences between patients and controls, which might illustrate the minor allele C may increase the risk for MSA (genotype, P = 0.006, OR = 1.245, 95% CI = [1.066-1.455]; allele, P = 0.001, OR = 1.887, 95% CI = [1.303-2.733]). For rs16944, patients carrying AA genotype showed a nearly 5-year early age at onset (AAO) than GG genotype (50.52 § 7.45 years vs. 54.90 § 7.21 years, P = 0.037). No differences were found in genotype distribution and MAF of the five SNPs between patients with MSA with predominant cerebellar ataxia (MSA-C) and with predominant Parkinsonism (MSA-P). Conclusion: Our study suggests that rs1799964 of TNF-a may act as a risk factor for MSA and the IL-1b rs16944 might be a genetic factor that modifies the AAO in MSA. Moreover, the exact mechanism of neuroinflammatory response in MSA deserves further exploration. [ABSTRACT FROM AUTHOR]

Objective: Mutations of the cyclin F (CCNF) gene were recently identified to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Western and Japanese populations. The rare protein-altering variants frequency is 0.6 to 3.3% in ALS and FTD from these diverse geographic populations while no systematic analysis of CCNF variants were conducted in the Chinese population. Methods: We screened all exons of CCNF in a cohort of 269 cases (including 181 ALS and 88 FTD) from Mainland China using Sanger sequencing. Results: A rare heterozygous variant (c.481G > A, p.G161R) was detected in a sporadic ALS case with a frequency of 0.6%, while no mutation was identified in patients with FTD. The same variant was also found in a sporadic ALS patient from America. Conclusions: Our result indicates that the mutation of CCNF is rare in patients with ALS and FTD from Mainland China. [ABSTRACT FROM AUTHOR]

Background: Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by poorly levodopa-responsive parkinsonism, cerebellar ataxia, and autonomic dysfunction. Pathogenic mechanisms remain obscure, but the neuropathological hallmark is the presence of α-synuclein-positive glial cytoplasmic inclusions. Previous studies suggested that a single nucleotide polymorphism (SNP), rs11931074, in the α-synuclein gene, SNCA, had highly significant association with an increased risk of the development of MSA in the Caucasian subjects. In contrast, a Korean study failed to identify an association with disease risk. Methods: To study the effect of rs11931074 on MSA risk in a Chinese population, we conducted a case–control study and genotyped SNP rs11931074 by Sanger sequencing in 96 Chinese patients with MSA and 120 healthy controls. Moreover, we performed a meta-analysis on the topic. Results: There was no statistical difference in genotypes or allele frequencies of SNP rs11931074 between MSA and control groups in our cohort. The results of meta-analysis showed that the risk allele T of rs11931074 was associated with MSA (pooled odds ratio = 1.26, 95% confidence interval = 1.07–1.49, P = 0.006). Conclusions: Despite a positive result of the meta-analysis, the significant difference in frequency of allele T of rs11931074 between Asian and Caucasian subjects indicates that population heterogeneity at rs11931074 may exist. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is the most common type of spinocerebellar ataxia in China. However, the pathogenesis of SCA3/MJD is still unknown. MicroRNAs (miRNAs) have been repeatedly demonstrated to exist in human peripheral serum in a bio-stable form and have been shown to be useful biomarkers for other neurodegenerative disorders. However, no study of SCA3/MJD patients has assessed specific changes in regulatory miRNAs. Therefore, we systematically used the miRCURYTM LNA Array, followed by quantitative real-time polymerase chain reaction validation, to access miRNA expression levels in the serums from SCA3/MJD patients. Our results show that miR-25, miR-125b, miR-29a, and miR-34b could be potential biomarkers for SCA3/MJD and could be used to further investigate the pathogenesis of SCA3/MJD and drug development. [ABSTRACT FROM AUTHOR]

Optogenetic technology, also known as optogenetics, is a novel multidisciplinary field in biotechnology that integrates genetic engineering, electrophysiology, and optical and electronic engineering. This recently developed technology has evolved rapidly and generated considerable excitement in neuroscience research. This technology successfully solves the severe problem of achieving both high temporal and spatial precision within intact neural tissues of animals that electrical stimulation and pharmacological methods cannot achieve. It allows neurons to express light-sensitive genes that enable the identification, dissection, and manipulation of specific neural populations and their connections in the tissues and organs of awake animals with unprecedented spatial and temporal precision. Light-sensitive genes chiefly including the genetically targeted light-gated channels channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR) cause intracellular ion flow during optical illumination. Subsequently, the neurons undergo a series of changes resulting from membrane depolarization or hyperpolarization. To date, there are many published research articles and reviews that describe this new technology; however, few of the reports concern its application to neuropsychiatric diseases. In this review, we summarize the most recent optogenetic research in these diseases, including Parkinson's disease (PD), epilepsy, schizophrenia, anxiety, fear, reward behaviors, and sleep disorders. We propose that novel optogenetics technology creates excellent opportunities for innovative treatment strategies of neuropsychiatric diseases. [ABSTRACT FROM AUTHOR]

Vitamin D and vitamin D receptor (VDR) have been postulated as environmental and genetic factors in neurodegenerative disorders including multiple sclerosis, Alzheimer disease, and recently Parkinson disease (PD). The purpose of this study is to explore the potential correlation between single nucleotide polymorphisms of the VDR gene (VDR) rs4334089 and rs731236 and PD. A total of 483 patients with PD and 498 age- and sex-matched controls were involved in this study. Genotypes were determined by using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. There were no significant differences in the genotype and allele frequencies of VDR rs4334089 and rs731236 polymorphisms between the group of patients with PD and the control group in a Chinese Han population (for VDR rs4334089: OR 1.02, 95% CI: 0.85-1.23; for VDR rs731236: OR 1.13, 95% CI: 0.75-1.71). Similarly, there were still no differences when stratifying by age or by gender. These findings suggest that VDR gene is not a susceptibility gene for PD in our population. [ABSTRACT FROM AUTHOR]

DNA methylation, which has been investigated extensively recently, has been studied in various human diseases, including cancer, and the analysis of DNA methylation has provided useful biomarkers for diagnosing cancer, monitoring treatment, and predicting the prognosis of cancer. Recently, aberrant DNA methylation has been reported in various neuropsychiatric diseases in both postmortem brains and peripheral blood cells. This review summarizes the current evidence on aberrant DNA methylation in peripheral blood cells from patients with neurodevelopmental, neurodegenerative, and psychiatric disorders, and we propose that DNA methylation could be a novel biomarker for these disorders. [ABSTRACT FROM AUTHOR]

Benign familial infantile seizures (BFIS) is an autosomal dominant epileptic syndrome characterized by afebrile partial seizures with or without secondary generalized tonic-clonic seizures beginning at three to ten months of age. Genetic studies have revealed three susceptibility chromosomal loci on 19q12-q13.1, 16p12-q12 and 2q24. Previously we described the novel locus on 1p36.12-p35.1 for a Chinese family affected with BFIS, and below is a subsequent mutation analysis of candidate genes for the mapped chromosome region. Forty-five genes were selected and subjected to mutation analysis. Thirty-six nucleotide variants were found, none of which led to pathogenic changes, thereby were identified as nucleotide polymorphisms. The analyses suggest those candidate genes that were detected might not be involved in the epileptogenesis of pure BFIS, at least in the Chinese family we studied. [ABSTRACT FROM AUTHOR]

Autosomal dominant cerebellar ataxias (ADCAs) are a clinically and genetically heterogeneous group of neurodegenerative disorders primarily affecting the cerebellum. Nearly 33 genetically distinct subtypes have been defined, and 19 seemingly unrelated disease genes have been identified so far. Recently, mutations in the ATPase family gene 3-like 2 (AFG3L2) gene were presented to cause SCA28 subtype. In order to define the frequency of SCA28 mutation in Chinese mainland, we performed molecular genetic analysis in 67 unrelated affected individuals with ADCA. At last, we did not find AFG3L2 gene mutation, except for three known single nucleotide polymorphisms (SNP)s. It suggests that SCA28 subtype is very rare in Chinese mainland. [ABSTRACT FROM AUTHOR]

We report on a Chinese family with three members who have CAG repeat expansion in the ataxin-3, two members present with expanded trinucleotide repeat in both the ataxin-3 and tata-binding protein ( TBP) and an individual who carries expanded CAG/CAA repeat in the TBP. Only the patients who carry an allele with expansion in the ataxin-3 gene presented with clinical symptoms. This interesting family presents a unique mutation state. We will continue to track this family in the future, which may help us further elucidate the pathogenic mechanism of spinocerebellar ataxia (SCA) type 3 and 17. The study also provides us a novel conception that mutations from two pathogenetic genes may coexist in one patient and SCA-affected patients with intermediate allele need to be further excluded for other SCA subtypes. [ABSTRACT FROM AUTHOR]