Diverse CMT2 neuropathies are linked to aberrant G3BP interactions in stress granules.

Complex diseases often involve the interplay between genetic and environmental factors. Charcot-Marie-Tooth type 2 neuropathies (CMT2) are a group of genetically heterogeneous disorders, in which similar peripheral neuropathology is inexplicably caused by various mutated genes. Their possible molecular links remain elusive. Here, we found that upon environmental stress, many CMT2-causing mutant proteins adopt similar properties by entering stress granules (SGs), where they aberrantly interact with G3BP and integrate into SG pathways. For example, glycyl-tRNA synthetase (GlyRS) is translocated from the cytoplasm into SGs upon stress, where the mutant GlyRS perturbs the G3BP-centric SG network by aberrantly binding to G3BP. This disrupts SG-mediated stress responses, leading to increased stress vulnerability in motoneurons. Disrupting this aberrant interaction rescues SG abnormalities and alleviates motor deficits in CMT2D mice. These findings reveal a stress-dependent molecular link across diverse CMT2 mutants and provide a conceptual framework for understanding genetic heterogeneity in light of environmental stress.

Profiling microRNA from peripheral blood mononuclear cells in early-onset familial Alzheimer's disease.

MicroRNAs (miRNAs) refer to short in-length, noncoding RNAs that regulate numerous cellular functions by targeting mRNA, and numerous types of research have shown that miRNA is vitalin Alzheimer's disease. For identifying differentially expressed miRNAs in the peripheral blood mononuclear cell (PBMC) of early-onset familial Alzheimer's disease (EOFAD), we conducted this study which might give a reference for potential therapeutic targets or biomarkers for this disease. On the basis of high-throughput sequencing, we screened the miRNAs expression profiles in PBMC regarding both EOFAD patients and healthy controls, and the biological information was analyzed. Compared with the PBMC of healthy controls, 142 miRNAs were differentially expressed in EOFAD patients ( P < 0.05), including 48 significantly differentially expressed miRNAs, 37 of which were significantly upregulated, including miR-3614-5p, miR-193A-5p, miR-2115-5p, miR-143-3p, etc. and 11 were significantly downregulated, including miR-484, miR-708-5p, miR-205-5p, miR-31-5p, etc. According to biological information analysis, 768 miRNA target genes were differentially expressed, which may be involved in multiple gene functions and cell cycle, cell senescence, and several signaling pathways, including FoxO, MAPK, Ras, mTOR, neurotrophin, etc. There are differential expressions of miRNAs in PBMC of EOFAD patients and controls, revealing their importance in Alzheimer's disease as indicated by co-expression network analysis; this may support basic information for new biomarkers or treatment exploring.

DAP12 deletion causes age-related motor function impairment but promotes functional recovery after sciatic nerve crush injury.

DNAX activating protein of 12 kDa (DAP12)-deficiency mice showed impaired differentiation of oligodendrocytes and reduced myelin in the central nervous system. Whether DAP12 is expressed by Schwann cells and its roles in the peripheral nervous system (PNS) remains unknown. In this study, expression of DAP12 was detected in Schwann cells in vivo and in vitro. The DAP12-knockout (KO) mice showed age-related motor deficits and thinner myelin in the sciatic nerve than WT mice but significantly faster clinical recovery after sciatic nerve crush injury. In sciatic nerves of DAP12 KO and WT mice, proteomic profiles analysis identified 158 differentially expressed proteins (DEPs) at 8-week-old, 29 DEPs at 54-week-old and 33 DEPs at two weeks after crush injury. Typically, of the DEPs at 54-week-old, up-regulated Lgmn and down-regulated RecK and Yap1 were associated with myelin loss in the sciatic nerve of DAP12 KO mice. Upregulation of nicotinamide nucleotide transhydrogenase and haptoglobin were associated with the accumulation of macrophages in the crushed sciatic nerve of DAP12 KO mice. After crush injury, there were significantly more M1 macrophages at one-week and more M2 macrophages at two-week in sciatic nerve of DAP12 KO mice than WT mice, indicating that DAP12 deletion promotes the phenotype conversion of macrophages from M1 to M2. Collectively, our findings suggest that DAP12 may exert dual roles in the PNS including promoting the physiological myelin formation and maintenance of Schwann cells but delaying nerve repair after injury by modulating the recruitment of macrophages and phenotype conversion.

Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer's Disease Mouse Model Carrying a PSEN1 p.G378E Mutation.

Objective To study the effects of TYRO protein kinase-binding protein (TYROBP) deficiency on learning behavior, glia activation and pro-inflammatory cycokines, and Tau phosphorylation of a new Alzheimer's disease (AD) mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation, and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice (PSEN1G378E/WT; Tyrobp+/-) and the homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp-/-). Water maze test was used to detect spatial learning and memory ability of mice. After the mice were sacrificed, the hippocampus was excised for further analysis. Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte. Western blot was used to detect the expression levels of Tau and phosphorylated Tau (p-Tau), and ELISA to measure the levels of pro-inflammatory cytokines. Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus. Absence of TYROBP in PSEN1G378E mutation mouse model prevented the deterioration of learning behavior, decreased the numbers of microglia and astrocytes, and the levels of interleukin-6, interleukin-1ß and tumor necrosis factor-α in the hippocampus (all P < 0.05). The ratios of AT8/Tau5, PHF1/Tau5, pT181/Tau5, pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp-/- mice) compared with PSEN1G378E/G378E mice (all P < 0.05). Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD. However, the relationship between neuroinflammation processes involving microglia and astrocyte activation, and release of pro-inflammatory cytokines, and p-Tau pathology needs further study.

Downregulation of m6A Methyltransferase in the Hippocampus of Tyrobp -/- Mice and Implications for Learning and Memory Deficits.

Loss-of-function mutations in the gene that encodes TYRO protein kinase-binding protein (TYROBP) cause Nasu-Hakola disease, a heritable disease resembling Alzheimer's disease (AD). Methylation of N6 methyl-adenosine (m6A) in mRNA plays essential roles in learning and memory. Aberrant m6A methylation has been detected in AD patients and animal models. In the present study, Tyrobp-/- mice showed learning and memory deficits in the Morris water maze, which worsened with age. Tyrobp-/- mice also showed elevated levels of total tau, Ser202/Thr205-phosphorylated tau and amyloid ß in the hippocampus and cerebrocortex, which worsened with aging. The m6A methyltransferase components METTL3, METTL14, and WTAP were downregulated in Tyrobp-/- mice, while expression of demethylases that remove the m6A modification (e.g., FTO and ALKBH5) were unaltered. Methylated RNA immunoprecipitation sequencing identified 498 m6A peaks that were upregulated in Tyrobp-/- mice, and 312 m6A peaks that were downregulated. Bioinformatic analysis suggested that most of these m6A peaks occur in sequences near stop codons and 3'-untranslated regions. These findings suggest an association between m6A RNA methylation and pathological TYROBP deficiency.

Effects of TYROBP Deficiency on Neuroinflammation of a Alzheimer's Disease Mouse Model Carrying a PSEN1 p.G378E Mutation / 中国医学科学杂志(英文版)

Objective To study the effects of TYRO protein kinase-binding protein (TYROBP) deficiency on learning behavior, glia activation and pro-inflammatory cycokines, and Tau phosphorylation of a new Alzheimer's disease (AD) mouse model carrying a PSEN1 p.G378E mutation.Methods A new AD mouse model carrying PSEN1 p.G378E mutation was built based on our previously found AD family which might be ascribed to the PSEN1 mutation, and then crossed with TYROBP deficient mice to produce the heterozygous hybrid mice (PSEN1G378E/WT; Tyrobp+/-) and the homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp-/-). Water maze test was used to detect spatial learning and memory ability of mice. After the mice were sacrificed, the hippocampus was excised for further analysis. Immunofluorescence was used to identify the cell that expresses TYROBP and the number of microglia and astrocyte. Western blot was used to detect the expression levels of Tau and phosphorylated Tau (p-Tau), and ELISA to measure the levels of pro-inflammatory cytokines. Results Our results showed that TYROBP specifically expressed in the microglia of mouse hippocampus. Absence of TYROBP in PSEN1G378E mutation mouse model prevented the deterioration of learning behavior, decreased the numbers of microglia and astrocytes, and the levels of interleukin-6, interleukin-1β and tumor necrosis factor-α in the hippocampus (all P < 0.05). The ratios of AT8/Tau5, PHF1/Tau5, pT181/Tau5, pT231/Tau5 and p-ERK/ERK were all higher in homozygous hybrid mice (PSEN1G378E/G378E; Tyrobp-/- mice) compared with PSEN1G378E/G378E mice (all P < 0.05). Conclusions TYROBP deficiency might play a protective role in the modulation of neuroinflammation of AD. However, the relationship between neuroinflammation processes involving microglia and astrocyte activation, and release of pro-inflammatory cytokines, and p-Tau pathology needs further study.

RNA-sequencing of peripheral blood circular RNAs in Parkinson disease.

BACKGROUND: Circular RNAs (circRNAs) play an important role in many neurological diseases and can serve as biomarkers for these diseases. However, the information about circRNAs in Parkinson disease (PD) remained limited. In this study, we aimed to determine the circRNAs expression profile in PD patients and discuss the significance of circRNAs in the diagnosis of PD. METHODS AND RESULTS: Using RNA-sequencing in peripheral blood RNAs, we showed that a significant number of mRNAs or circRNAs were differentially expressed between PD patients and normal controls (NCs), which included 273 up-regulated and 493 down-regulated mRNAs, and 129 up-regulated and 282 down-regulated circRNAs, respectively. Functional analysis was performed using the Kyoto Encyclopedia of Gene and Genomes (KEGG) pathway analysis, and the results showed that the second most enriched KEGG pathway was PD. These data suggest that the levels of mRNAs and circRNAs in peripheral blood could be potentially used as biomarkers for PD. In addition, we correlated mRNAs and circRNAs by constructing a competing endogenous RNA (ceRNA) network in PD. The resulted-in ceRNA network included 10 differentially expressed mRNAs from PD pathway, 13 predicted miRNAs, and 10 differentially expressed circRNAs. CONCLUSION: Collectively, we first characterized the expression profiles of circRNAs and mRNAs in peripheral blood from PD patients and proposed their possible characters in the pathogenesis of PD. These results provided valuable insights into the clues underlying the pathogenesis of PD.

Profiling of differentially expressed circular RNAs in peripheral blood mononuclear cells from Alzheimer's disease patients.

Expression of circular RNA (circRNA), a class of noncoding RNAs that regulates gene expression, is altered in Alzheimer's disease. This study profiled differentially expressed circRNAs in peripheral blood mononuclear cells (PBMCs) from five patients with Alzheimer's disease compared to healthy controls using circRNA microarrays. We identified a total of 4060 differentially expressed circRNAs (1990 upregulated and 2070 downregulated) in Alzheimer's disease patients. Among these circRNAs, 10 randomly selected circRNAs were verified using qRT-PCR. The top 10 upregulated and downregulated circRNAs were used to predict their target miRNAs. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that these differentially expressed circRNAs were strongly associated with inflammation, metabolism, and immune responses, which are all risk factors for Alzheimer's disease. The circRNA-miRNA-mRNA network was most involved in the MAPK, mTOR, AMPK, and WNT signaling pathways in Alzheimer's disease. In conclusion, the current study demonstrated the importance of circRNAs in Alzheimer's disease development. Future studies will evaluate some of these circRNAs as biomarkers for early disease detection and to develop therapeutic strategies to clinically control Alzheimer's disease progression.

Oxymatrine can attenuate pathological deficits of Alzheimer's disease mice through regulation of neuroinflammation.

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive learning and cognitive damage. Several hypotheses such as amyloid cascade hypothesis, hyper-phosphorylated τ hypothesis, and energy metabolism hypothesis have been proposed to elucidate the disease. However, the exact mechanism of AD remains unclear and current therapeutic strategies are miserable. Cumulative evidence showed that neuroinflammation plays a significant role in the pathogenesis of the AD. Oxymatrine (OMT), a plant-derived bioactive compound, has anti-viral, anti-fibrosis, and anti-tumor effects through the involvement of several immune-related signaling pathways. Whether OMT can attenuate the pathology of AD is largely unknown. In this manuscript, we found that treatment of OMT can significantly improve cognitive and learning abilities of AD mice during various behavioral test. Treatment of OMT can significantly reduce the densities of Aß plaques and astrocyte clusters in the neocortex and hippocampus of AD mice. Furthermore, treatment of OMT significantly reduced the concentration of pro-inflammatory cytokines including IL-6, IL-1ß, TNF-α and IL-17A in AD mice. Taken together, our data indicate that OMT may serve as a potential drug for AD.

Comparative study of microRNA profiling in one Chinese Family with PSEN1 G378E mutation.

MicroRNAs are not widely studied in familial Alzheimer's disease cases, whether the microRNA profilings in familial Alzheimer's disease patients are similar to the sporadic AD patients is not known. This study aims to investigate the differential expression of microRNAs (miRNAs) associated with early-onset familial Alzheimer's disease (EO-FAD) in a Chinese family. We performed the gene mutation analysis in a family clinically diagnosed of EO-FAD. Micro-arrays were used to profile the miRNAs in cerebrospinal fluid of 2 affected members, 2 unaffected carriers and 2 mutation negative controls. The clinical presentation confirmed the EO-FAD diagnosis, and a recurrent mutation of the PSEN1 p.G378E was found in the family. The result showed that in the miRNAs expression profile, a total of 166 miRNAs were up-regulated and 3 miRNAs were down-regulated in the affected individuals compared with mutation negative individuals. But after Benjamini Hochberg FDR correction, only 25 miRNAs were significantly up-regulated and no miRNA was down-regulated, the levels of miR-30a-5p, miR-4758-3p and let-7a-3p were elevated significantly. Compared with mutation negative controls, 21 miRNAs were up-regulated and 18 microRNAs were down-regulated in the unaffected mutation carriers, after Benjamini Hochberg FDR correction, miR-345-5p was up-regulated and miR-4795-3p was down-regulated in the unaffected mutation carriers. And there was no difference between the affected members and unaffected mutation carriers. GO database showed that the top biological processes affected by the predicted target genes are nucleic acid binding transcription factor activity and transcription factor activity (sequence-specific DNA binding) (GO:0001071 and GO:0003700). The result of KEGG pathways showed 64 pathways were implicated in the regulatory network. The present study identified the miRNA profiling of Chinese siblings with G378E mutation in the PSEN1. Compared with mutation negative controls, the levels of 25 miRNAs including miR-30a-5p, miR-4758-3p and let-7a-3p were elevated significantly in the affected members, miR-345-5p was up-regulated and miR-4795-3p was down-regulated in the unaffected mutation carriers. Our study showed the microRNA profilings in the cases of a EO-FAD family with PSEN1 p.G378E mutation, but because of the individuals in the family was small, the results in other types of EO-FAD still need further studied.

Coexistence of Lambert-Eaton myasthenic syndrome and autoimmune encephalitis with anti-CRMP5/CV2 and anti-GABAB receptor antibodies in small cell lung cancer: A case report.

RATIONALE: Autoimmune encephalitis and Lambert-Eaton myasthenic syndrome are classic paraneoplastic neurological conditions common in patients with small cell lung cancer. PATIENT CONCERNS: The patient complained of tiredness, fluctuating recent memory loss, and inability to find his home. His family members reported a change in character, irritability, and paranoia. One month later, the patient had 1 grand mal seizure lasting 5 minutes. DIAGNOSIS: The patient was diagnosed with limbic encephalitis combined with Lambert-Eaton myasthenic syndrome. The gamma-aminobutyric acid B (GABAB) receptor and collapsin response mediator protein 5 (CRMP5, also called CV2) antibody test results were positive. Nine months after the onset of symptoms, the patient was diagnosed with small cell lung cancer. INTERVENTIONS: The patient was administered intravenous immunoglobulin for 5 days. He was then treated with 60 mg prednisone once per day. The prednisone dose was gradually reduced by 1 tablet every 2 weeks. After the diagnosis, the patient underwent 6 courses of chemotherapy with cisplatin combined with sequential chemoradiation therapy. OUTCOMES: The patient was able to take care of himself. Neurological examination revealed a lower limb proximal muscle strength level of 4 and a reduced limb tendon reflex. The patient had deficits in short-term memory, a Mini-Mental State Examination score of 26, Montreal Cognitive Assessment score of 24, Self-rating Depression Scale score of 54 (mild depression), and Self-Rating Anxiety Scale score of 42 (normal). LESSONS: Autoimmune diseases of the peripheral and central nervous systems can be observed at the same time in patients with small cell lung cancer, even when magnetic resonance imaging findings are negative and immune therapy is effective.

MicroRNA-132 protects hippocampal neurons against oxygen-glucose deprivation-induced apoptosis.

Hypoxic-ischemic brain injury (HIBI) results in death or long-term neurologic impairment in both adults and children. In this study, we investigated the effects of microRNA-132 (miR-132) dysregulation on oxygen-glucose deprivation (OGD)-induced apoptosis in fetal rat hippocampal neurons, in order to reveal the therapeutic potential of miR-132 on HIBI. MiR-132 dysregulation was induced prior to OGD exposure by transfection of primary fetal rat hippocampal neurons with miR-132 mimic or miR-132 inhibitor. The effects of miR-132 overexpression and suppression on OGD-stimulated hippocampal neurons were evaluated by detection of cell viability, apoptotic cells rate, and the expression of apoptosis-related proteins. Besides, TargetScan database and dual luciferase activity assay were used to seek a target gene of miR-132. As a result, miR-132 was highly expressed in hippocampal neurons following 2 h of OGD exposure. MiR-132 overexpression significantly increased OGD-diminished cell viability and reduced OGD-induced apoptosis at 12, 24, and 48 h post-OGD. MiR-132 overexpression significantly down-regulated the expressions of Bax, cytochrome c, and caspase-9, but up-regulated BCl-2. Caspase-3 activity was also significantly decreased by miR-132 overexpression. Furthermore, FOXO3 was a direct target of miR-132, and it was negatively regulated by miR-132. To conclude, our results provide evidence that miR-132 protects hippocampal neurons against OGD injury by inhibiting apoptosis.

Interactions between four gene polymorphisms and their association with patients with Parkinson's disease in a Chinese Han population.

The four previously reported Parkinson's disease (PD)-related single-nucleotide polymorphisms (SNPs) - rs1775143, rs823114, rs2071746 and rs62063857 - have rarely been studied in Chinese Han populations. To examine the association between these SNPs and PD, we conducted a case-control study of 158 patients with PD and 210 controls. All participants were Chinese Han from Northern China. With covariate adjustment for clinical characteristics, logistic regression analysis revealed no differences in genotype or allele frequencies for the four SNPs. Stratified by age of disease onset, sex, smoking status, duration of disease, baseline UPDRS, Hoehn-Yahr Stage, PD subtypes, scores of Hamilton anxiety scale, Hamilton depression scale and activity of daily living, all of the p values did not remain significant after Bonferroni correction. However, the haplotype rs1775143T-rs823114G-rs2071746T-rs62063857A was associated with increased risk of developing PD (p = 0.003, OR = 456.88, 95% CI: 27.40-7619.75) in our case-control sample set. The haplotype rs1775143T-rs823114G-rs2071746T was also associated with increased risk of developing PD (p = 0.003, OR = 338.43, 95% CI: 20.68-5538.27). Although the haplotype rs1775143T-rs823114G-rs62063857A was associated with increased risk of PD (p = 0.03), the 95% CI was 0.993-22.469. Our data demonstrate that although specific SNPs were not related with PD patients, certain haplotypes were associated with increased risk for PD in the Chinese Han population. These results provide further evidence that the etiology of PD is multifactorial, although the underling mechanism needs further study.

Memory B cells in Guillain-Barré syndrome.

IgG autoantibodies against gangliosides show the highest titers at the disease onset of axonal Guillain-Barré syndrome (GBS), in which there are no IgM anti-ganglioside antibodies. We hypothesized that memory B cells take part in the development of producing IgG autoantibodies. In this study, we analyzed the memory B cells in patients with GBS using flow cytometry. There was significantly higher percentage of memory B cells in patients with GBS than the healthy controls. The Spearman correlation analysis demonstrated that increased percentage of memory B cells was positively correlated with the clinical severity of the patients with GBS. Our study provides the evidences that memory B cells may be involved in mechanism of GBS.

IgG-degrading enzyme of Streptococcus pyogenes (IdeS) prevents disease progression and facilitates improvement in a rabbit model of Guillain-Barré syndrome.

Autoantibodies binding to peripheral nerves followed by complement deposition and membrane attack complex formation results in nerve damage in Guillain-Barré syndrome (GBS). Strategies to remove the pathogenic autoantibodies or block the complement deposition benefit most patients with GBS. Immunoglobulin G-degrading enzyme of Streptococcus pyogenes (IdeS) is a cysteine protease which cleaves IgG antibodies into F(ab')2 and Fc fragments. In this study, using a rabbit model of axonal GBS, acute motor axonal neuropathy (AMAN), we demonstrated that IdeS treatment significantly reduced the disruption of Nav channels as well as activated C3 deposition at the anterior spinal root nodes of Ranvier in AMAN rabbits. IdeS significantly promoted the clinical recovery of AMAN rabbits and there were significant lower frequencies of axonal degeneration in anterior spinal roots of AMAN rabbits with IdeS treatment compared to the saline controls. Our data support that IdeS treatment is a promising therapeutic strategy for GBS.

Mitochondrial mutations in 12S rRNA and 16S rRNA presenting as chronic progressive external ophthalmoplegia (CPEO) plus: A case report.

RATIONALE: Chronic progressive external ophthalmoplegia (CPEO) is a classical mitochondrial ocular disorder characterized by bilateral progressive ptosis and ophthalmoplegia. Kearns -Sayre syndrome (KSS) is a multisystem disorder with PEO, cardiac conduction block, and pigmentary retinopathy. A few individuals with CPEO have other manifestations of KSS, but do not meet all the clinical diagnosis criteria, and this is called "CPEO plus." PATIENT CONCERNS: We report a 48-year-old woman exhibiting limb weakness, ptosis, ophthalmoparesis, and cerebellar dysfunctions. DIAGNOSES: The patient was diagnosed as exhibiting CPEO plus syndrome. INTERVENTIONS: The patient underwent clinical, genetic, histological, and histochemical analysis. She was treated orally with CoQ10, vitamin Bs, L-carnitine, and vitamin E. OUTCOMES: The patient's serum creatine kinase levels, electrocardiography, and nerve conduction study results were normal; an electromyogram revealed myopathic findings. Magnetic resonance imaging showed global brain atrophy, particularly in the brainstem and cerebellum areas. A muscle biopsy showed the presence of abundant ragged red fibers. Sequencing of the mitochondrial DNA from the skeletal muscle biopsy revealed C960del mutation in 12S rRNA and homozygous mutation C2835T in 16S rRNA. She took medicines on schedule, the clinical features were similar as 2 years ago. LESSONS: This is the first report of 2 rRNA mutations in a patient with MRI findings showing global brain atrophy, particularly in brainstem and cerebellum areas. Early recognition and appropriate treatment is crucial. This case highlights the cerebellar ataxia can occur in CPEO plus.

MicroRNA expression profiling in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is an acute inflammatory autoimmune disease affecting the peripheral nervous system. MicroRNAs (miRNAs) are a class of small noncoding RNAs that play critical roles in the process of various diseases. The miRNAs in GBS were less studied. In this study, using microarray technology, we found two miRNAs including has-miR-4717-5p and has-miR-642b-5p were upregulated in patients with GBS, which were further confirmed by PCR analysis. Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that the dysregulated miRNAs may be involved in the mechanism of GBS by affecting the cellular differentiation, cell survival and axonal outgrowth.

Polygenic determinants of Parkinson's disease in a Chinese population.

It has been reported that some single-nucleotide polymorphisms (SNPs) are associated with the risk of Parkinson's disease (PD), but whether a combination of these SNPs would have a stronger association with PD than any individual SNP is unknown. Sixteen SNPs located in the 8 genes and/or loci (SNCA, LRRK2, MAPT, GBA, HLA-DR, BST1, PARK16, and PARK17) were analyzed in a Chinese cohort consisting of 1061 well-characterized PD patients and 1066 control subjects from Central South of Mainland China. We found that Rep1, rs356165, and rs11931074 in SNCA gene; G2385R in LRRK2 gene; rs4698412 in BST1 gene; rs1564282 in PARK17; and L444P in GBA gene were associated with PD with adjustment of sex and age (p < 0.05) in the analysis of 16 variants. PD risk increased when Rep1 and rs11931074, G2385R, rs1564282, rs4698412; rs11931074 and G2385R, rs1564282, rs4698412; G2385R and rs1564282, rs4698412; and rs1564282 and rs4698412 were combined for the association analysis. In addition, PD risk increased cumulatively with the increasing number of variants (odds ratio for carrying 3 variants, 3.494). In summary, we confirmed that Rep1, rs356165, and rs11931074 in SNCA gene, G2385R in LRRK2 gene, rs4698412 in BST1 gene, rs1564282 in PARK17, and L444P in GBA gene have an independent and combined significant association with PD. SNPs in these 4 genes have a cumulative effect with PD.

Marginal association between SNP rs2046571 of the HAS2 gene and Parkinson's disease in the Chinese female population.

Recent GWASs have implicated many novel SNPs in the development of Parkinson's disease (PD). Single nucleotide polymorphism (SNP) rs2046571 of the HSA2 (encoding hyaluronan synthase 2) was reported to have marginal association with PD. Herein, we conducted a case-control study to evaluate the possible association between SNP rs2046571 and PD in Chinese. All subjects (1043 PD patient and 1044 normal control) were successfully genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No statistically significant difference in genotype frequency between cases and controls was observed (P=0.074), no statistically significant difference in genotype frequency between early-onset and late-onset was observed (P=0.264 and P=0.120, respectively). No statistically significant difference in genotype frequency between male cases and controls (P=0.108). But surprisingly, there was statistically marginal significant difference in genotype frequency between female cases and controls (P=0.042). Our findings suggested that rs2046571 of the HSA2 has marginal association with PD in Chinese population.

Analysis of EIF4G1 in ethnic Chinese.

BACKGROUND: Eukaryotic translation initiation factor 4-gamma 1 (EIF4G1) gene mutations have recently been reported in autosomal dominant, late-onset Parkinson's disease (LOPD). We carried out genetic analysis to determine the prevalence of EIF4G1 variants in an ethnic Chinese population and to better understand the association between EIF4G1 and PD. METHODS: We conducted a comprehensive genetic analysis of EIF4G1 in a cohort of 29 probands of autosomal dominant, LOPD families. Polymerase chain reaction (PCR) analysis and sequencing was carried out of the entire EIF4G1 exonic regions and exon-intron boundaries. Specific mutation and exonic variants were chosen for further sequencing in a case-control study including 503 sporadic PD and 508 healthy controls. Statistical significance was analyzed by the Chi-square test. RESULTS: Our analysis revealed three exonic variants (rs2230571, rs13319149 and rs2178403) and eight intronic variants across the entire EIF4G1 gene. No reported mutations were detected in EIF4G1 exonic regions. The synonymous coding variant rs2230571 in exon 27 and the eight intronic variants were not used for further sequencing, but the specific mutation c.3614G > A (p.R1205H) and the two nonsynonymous variants (rs13319149 and rs2178403) were chosen for further analysis in a case-control study. None of the 503 sporadic PD or 508 healthy controls carried p.R1205H, and there was no statistical significance in rs2178403 genotype or allele frequencies in EIF4G1 between the PD cases and the healthy controls (p = 0.184 and p = 0.774, respectively; Chi-square test). The rs13319149 genotype in all PD cases and healthy controls was GG. CONCLUSIONS: Our data indicate that in an ethnic Chinese population, the pathogenic mutation p.R1205H in EIF4G1 is not common and that EIF4G1 exonic variants rs2178403 and rs13319149 are not associated with PD. EIF4G1 does not appear to be a frequent cause of PD in this ethnic Chinese population.