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2.
Hum Mol Genet ; 2021 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-33749734

RESUMO

GGGGCC repeats in a non-coding region of the C9orf72 gene have been identified as a major genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We previously showed that the GGGGCC expanded repeats alone were sufficient to cause neurodegeneration in Drosophila. Recent evidence indicates that GGGGCC expanded repeats can modify various gene transcriptomes. To determine the role of these genes in GGGGCC-mediated neurotoxicity, we screened an established Drosophila model expressing GGGGCC expanded repeats in this study. Our results showed that knockdown of the DNA topoisomerase II (Top2) gene can specifically modulate GGGGCC-associated neurodegeneration of the eye. Furthermore, chemical inhibition of Top2 or siRNA-induced Top2 downregulation could alleviate the GGGGCC-mediated neurotoxicity in Drosophila assessed by eye neurodegeneration and locomotion impairment. By contrast, upregulated Top2 levels were detected in Drosophila strains, and moreover, TOP2A level was also upregulated in Neuro-2a cells expressing GGGGCC expanded repeats, as well as in the brains of Sod1G93A model mice. This indicated that elevated levels of TOP2A may be involved in a pathway common to the pathophysiology of distinct ALS forms. Moreover, through RNA-sequencing, a total of 67 genes, involved in the pathways of intracellular signaling cascades, peripheral nervous system development, et al, were identified as potential targets of TOP2A to modulate GGGGCC-mediated neurodegeneration.

4.
Stem Cell Res ; 53: 102289, 2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33761381

RESUMO

Urine epithelial cells were harvested from a 32-year old female patient with spinocerebellar ataxia type 3 (SCA3) and reprogrammed into induced pluripotent stem cells (iPSCs) by non-integration system. The SCA3 derived iPSCs line, CSUXHi005-A, maintained 76 CAG expansions in the ATXN3 gene, was characterized by the expression of pluripotency markers and normal karyotype. The newly generated iPSCs retain the ability to differentiate into three germ layers by teratoma test, which provide an ideal tool for disease modeling, drug screening, and cellular therapy.

5.
Neurol India ; 69(1): 115-118, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642281

RESUMO

Context: A host of microRNAs have been reported to suppress tumor growth, invasion, and metastasis and play roles in neurodegeneration disorders. Moreover, microRNA changes are found in the peripheral blood, cerebrospinal fluid (CSF), and brain tissues of central nervous system diseases, including glioma, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and depression. Compared with other body fluids, CSF can reflect the brain pathological processes more accurately. Aims: To understand whether microRNA expression may be misregulated in patients with PD, and further discover potential diagnostic biomarkers and promising therapeutic targets for PD. Materials and Methods: Here, through real-time reverse-transcription polymerase chain reaction (RT-PCR), we compared CSF microRNA from 15 PD patients, 11 AD patients, and 16 controls with other neurologic disorders, such as encephalitis and Guillain-Barre syndrome. Results: Finally, we identified hsa-miR-626 changes in the CSF of PD patients. The mean expression level of hsa-miR-626 was significantly reduced in the CSF of PD patients compared with AD patients and controls. Conclusions: Our approach provides a preliminary research for identifying biomarkers in the CSF that could be used for the detection, diagnosis, and monitoring of PD.

7.
Parkinsonism Relat Disord ; 84: 29-34, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33548880

RESUMO

INTRODUCTION: A recent study reported that rare variants in NUS1 were associated with Parkinson's disease (PD). We aimed to assess the relative contribution of rare and common coding/non-coding variants of NUS1 to late-onset PD patients (LOPD). METHODS: Whole genome sequencing data were analyzed for target NUS1 regions, derived from a cohort of 1962 cases and 1279 controls. The genetic association analyses were performed using logistic regression analysis and Sequence Kernel association test. Expression quantitative trait loci (eQTL) analysis was conducted to further explore the association of variants with NUS1 expression based on the data from GTEx database. RESULTS: We identified 18 rare coding variants. p.Y131C was first identified in LOPD. However, no significant burden of rare NUS1 coding variants in LOPD was found. The rare variant sets of two regulatory elements (GH06J117605 and GH06J117674) were significantly enriched in LOPD even after Bonferroni correction (adjusted P = 0.013; adjusted P = 0.010). Considering the joint effect of rare and common variants, all variant sets within GH06J117605 and GH06J117674 showed association with LOPD but were no longer significant after Bonferroni correction. None of the common variants within coding/non-coding regions were significant after Bonferroni correction. The eQTL results suggested these variants in GH06J117605 and GH06J117674 could potentially have eQTL effects on the brain tissues. CONCLUSIONS: These findings provide novel insight into the role of NUS1 regulatory regions in the development of LOPD and indicate that the variants in regulatory elements of NUS1 may be associated with LOPD by influencing the gene expression level.

8.
Nat Med ; 27(3): 411-418, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33462448

RESUMO

Animal studies implicate meningeal lymphatic dysfunction in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (PD). However, there is no direct evidence in humans to support this role1-5. In this study, we used dynamic contrast-enhanced magnetic resonance imaging to assess meningeal lymphatic flow in cognitively normal controls and patients with idiopathic PD (iPD) or atypical Parkinsonian (AP) disorders. We found that patients with iPD exhibited significantly reduced flow through the meningeal lymphatic vessels (mLVs) along the superior sagittal sinus and sigmoid sinus, as well as a notable delay in deep cervical lymph node perfusion, compared to patients with AP. There was no significant difference in the size (cross-sectional area) of mLVs in patients with iPD or AP versus controls. In mice injected with α-synuclein (α-syn) preformed fibrils, we showed that the emergence of α-syn pathology was followed by delayed meningeal lymphatic drainage, loss of tight junctions among meningeal lymphatic endothelial cells and increased inflammation of the meninges. Finally, blocking flow through the mLVs in mice treated with α-syn preformed fibrils increased α-syn pathology and exacerbated motor and memory deficits. These results suggest that meningeal lymphatic drainage dysfunction aggravates α-syn pathology and contributes to the progression of PD.


Assuntos
Drenagem , Vasos Linfáticos/fisiopatologia , Meninges/fisiopatologia , Doença de Parkinson/fisiopatologia , Progressão da Doença , Humanos , Imagem por Ressonância Magnética , Meninges/diagnóstico por imagem , Doença de Parkinson/metabolismo , Doença de Parkinson/terapia , alfa-Sinucleína/metabolismo
9.
Neurosci Lett ; 740: 135441, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33184037

RESUMO

BACKGROUND: A recent study on early onset Parkinson's disease (PD) revealed that NUS1 is a risk gene for PD. Clinically, essential tremor (ET) is closely related to PD. In this study, we aimed to detect NUS1 variants and assess the effect of those variants on patients with ET. METHODS: The 5 coding regions and the exon-intron boundaries of NUS1 were directly sequenced in 395 patients with ET and an equal number of healthy controls, matched for age and sex. The function of variants was assessed by pathogenic predictive software programs. Genetic analysis of variants was used to evaluate susceptibility to ET. RESULTS: A total of 6 exonic variants were identified, including 3 synonymous and 3 missense variants. The non-synonymous variants were predicted to be tolerable. No variants had significant association with ET (none of the p-values were less than 0.05, using Fisher's exact test). CONCLUSION: Our study suggested that NUS1 variants may not contribute to the risk of ET.

10.
Exp Neurol ; 337: 113573, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33347831

RESUMO

Polyglutamine (polyQ) diseases are a group of neurodegenerative disorders involving expanded CAG repeats in pathogenic genes that are translated into extended polyQ tracts and lead to progressive neuronal degeneration in the affected brain. To date, there is no effective therapy for these diseases. Due to the complex pathologic mechanisms of these diseases, intensive research on the pathogenesis of their progression and potential treatment strategies is being conducted. However, animal models cannot recapitulate all aspects of neuronal degeneration. Pluripotent stem cells (PSCs), such as induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), can be used to study the pathological mechanisms of polyQ diseases, and the ability of autologous stem cell transplantation to treat these diseases. Differentiated PSCs, neuronal precursor cells/neural progenitor cells (NPCs) and mesenchymal stem cells (MSCs) are valuable resources for preclinical and clinical cell transplantation therapies. Here, we discuss diverse stem cell models and their ability to generate neurons involved in polyQ diseases, such as medium spiny neurons (MSNs), cortical neurons, cerebellar Purkinje cells (PCs) and motor neurons. In addition, we discuss potential therapeutic approaches, including stem cell replacement therapy and gene therapy.

11.
Neurobiol Aging ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33279242

RESUMO

The PLA2G6 gene has been identified as a causative gene for autosomal recessive early-onset dystonia-parkinsonism. Possible association was reported between single heterozygous PLA2G6 mutation and the risk of Parkinson's disease (PD), which, however, remained inconclusive. To clarify the effect of heterozygous PLA2G6 variants on the risk of PD, a total of 3710 patients with PD and 2636 controls of Chinese mainland population were recruited and genotyped by whole-exome sequencing or whole-genome sequencing. Variants in the PLA2G6 coding region were extracted and subjected to burden analysis using the optimal sequence kernel association test. In total, we identified 86 rare heterozygous variants in the PLA2G6 coding region, whereas no significant difference was found between cases and controls. Therefore, we found no supportive evidence for heterozygous PLA2G6 variants being a risk factor for PD in Chinese mainland population.

12.
Neurotoxicology ; 82: 100-107, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33249123

RESUMO

BACKGROUND: The influence of chronic arsenic exposure on cognitive impairment has been explored broadly by previous studies. However, most of them focused mainly on children rather than adults. In addition, in China, studies in this field are not sufficient. To illustrate how long-term arsenic exposure affects cognitive function, we designed a cross-sectional study involving 1556 adults. METHODS: All of them came from three locations around the Realgar Plant. The cognitive function of the participants was evaluated using a Chinese version of the Mini-mental state Examination (MMSE). The participants' internal arsenic exposure status (hair arsenic concentrations) and the external arsenic exposure status (the distance between the participants' location of residence and the Realgar Plant) were measured. RESULTS: Our research revealed that both of hair arsenic concentrations and the prevalence of arsenicosis, two important indexes, were significantly higher in the cognitive-impaired (CI) group than in the cognitive-normal (CN) group (P < 0.05). In addition, distance from the Realgar Plant was positively correlated with the MMSE scores and was negatively correlated with the prevalence of cognitive impairment. Moreover, our results demonstrated that there was a negative correlation between hair arsenic concentrations and MMSE scores. We conducted a two-level Logistic regression analysis and further confirmed that even after adjusting for potential confounding variables, arsenicosis retained a risk factor for cognitive impairment (odds ratio (OR) = 1.84, P < 0.05). CONCLUSIONS: Our results indicated that chronic arsenic exposure could impair adults' cognitive function in a dose-dependent manner. Additionally, arsenicosis could be an independent risk factor for cognitive impairment.

13.
Eur J Neurosci ; 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33226711

RESUMO

Recent studies have suggested that rare variants in MFSD8 contribute to risk for frontotemporal dementia (FTD). Considering the common underlying pathogenesis and the shared genetic risk between amyotrophic lateral sclerosis (ALS) and FTD, we screened the coding region of MFSD8 in 551 unrelated patients with ALS (510 unrelated sporadic ALS and 41 familial ALS probands) from mainland China by whole-exome sequencing to assess its mutation frequency in patients with ALS and evaluate its association. Two rare deleterious variants, c.343G>A (p. V115M) and c.695T>C (p.L232P), were identified in this study. The variant c.695T>C (p.L232P) has not been previously reported and the carrier of this variant exhibits a relatively younger age of disease onset. Our studies provide some independent evidence showing that the rare variant p.L232P in MFSD8 might be a candidate risk factor for ALS. However, the relatively small sample size and the lack of patient-derived cells limit the power of the genetic exploration of this study, further robust multicenter studies with larger sizes and biological experiments with patient-derived cells are needed to elucidate the pathogenesis of the rare variant in MFSD8 in ALS.

14.
Aging (Albany NY) ; 122020 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-33232267

RESUMO

The dominantly inherited spinocerebellar ataxias (SCAs) are a large class of neurodegenerative diseases. Transcranial magnetic stimulation has been used to evaluate the function of the pyramidal tract, and central motor conduction time (CMCT) is one index used to detect pyramidal tract dysfunction. We conducted a comprehensive search of PubMed, Embase and Web of Science. Eight eligible studies were included in the meta-analysis. For upper limb CMCT, the mean difference (95% confidence interval (CI)) between the combined SCA group and the control group was 2.24 [1.76-2.72], while the mean differences (95% CIs) between the subtypes and the control group were as follows: 4.43 [3.58-5.28] for SCA1, 0.25 [-0.15,0.65] for SCA2, 1.04 [-0.37,2.46] for SCA3 and 0.49 [-0.29,1.28] for SCA6. Additionally, SCA1 significantly differed from SCA2 and SCA3 in terms of CMCT (P=0.0006 and P=0.010, respectively). We also compared lower limb CMCT between the SCA2 and control groups. The mean difference (95% CI) was 6.58 [4.49-8.67], which was clearly statistically significant. The differences in CMCT values among different subtypes suggests diverse pathological mechanisms. In general, CMCT is a promising objective index to judge the severity of disease deserving further investigation.

15.
Neurosci Lett ; : 135510, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33221475

RESUMO

OBJECTIVE: This study aimed to investigate factors modulating spinocerebellar ataxia type 3 (SCA3) phenotype severity besides the expanded CAG repeats (ExpCAG) of ATXN3. METHODS: Data regarding CAG trinucleotide repeats, age at onset (AO), duration, age, sex, transmitting parent, and scale scores of SCA3 patients were collected. Multiple linear regression analysis was performed to identify influential independent variables. Age, AO, ExpCAG, and duration were considered control variables to analyze the correlation between independent variables and scale scores. RESULTS: Duration, age, and ExpCAG were screened as influential independent variables (P = 0.000). Age had the greatest impact on multiple linear regression models (P<5E-8). ExpCAG and SARA/ICARS/INAS/Barthel index were not correlated (P > 0.05); considering only age as the control, ExpCAG was slightly-to-moderately correlated with all aforementioned scores except INAS (P < 0.05). Age and all scores, except INAS, were positively correlated (P < 0.05); considering duration, AO, or ExpCAG as controls, their correlations did not change significantly. On controlling age, AO was negatively correlated with all scores (P < 0.05), except for the Barthel index (P > 0.05). Furthermore, the interaction model revealed that the interaction between age, duration, and ExpCAG was significantly associated with SCA3 disease severity (P < 0.05). CONCLUSION: Age is a potentially important modifier of SCA3 phenotype severity, through the interaction between ExpCAG and aging factors.

16.
Front Aging Neurosci ; 12: 584801, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240075

RESUMO

The genes involved in the metabolic pathways of amyloid-ß (Aß) and tau proteins significantly influence the etiology of Alzheimer's disease (AD). Various studies have explored the associations between some of these genes and AD in the Caucasian population; however, researches regarding these associations remain limited in the Chinese population. To systematically evaluate the associations of these genes with AD, we investigated 19 genes involved in the metabolism of Aß and tau based on previous studies selected using the PubMed database. This study included 372 patients with sporadic late-onset AD (sLOAD) and 345 cognitively healthy individuals from southern China. The results were replicated in the International Genomics of Alzheimer's Project (IGAP). Protein-protein interactions were determined using the STRING v11 database. We found that a single-nucleotide polymorphism, rs11682128, of BIN1 conferred susceptibility to sLOAD after adjusting for age, sex, and APOE ε4 status and performing the Bonferroni correction {corrected P = 0.000153, odds ratio (OR) [95% confidence interval (CI)] = 1.403 (1.079-1.824)}, which was replicated in the IGAP. Protein-protein interactions indicated that BIN1 was correlated with MAPT. Moreover, rare variants of NEP and FERMT2 (0.0026 < corrected P < 0.05), and the Aß degradation, tau pathology, and tau phosphatase pathways (0.01 < corrected P < 0.05), were nominally significantly associated with sLOAD. This study suggested that the genes involved in the metabolic pathways of Aß and tau contributed to the etiology of sLOAD in the southern Han Chinese population.

17.
Front Neurol ; 11: 577874, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240202

RESUMO

Background: Rapid eye movement sleep behavior disorder (RBD) is thought to be a prodromal symptom of Parkinson's disease (PD). RBD is also thought to be involved in cognitive decline and dementia in PD. In PD, although the relationship between RBD and cognitive dysfunctions was confirmed by considerable studies, whether RBD was associated with distinct types of cognitive defects is worth of study. Objectives: This systematic review summarizes the evidence relating to cognitive dysfunction in PD patients with RBD (PD-RBD) and those without and explores their specificity to cognitive domains. Methods: A meta-analysis using a random-effects model was performed for 16 different cognitive domains, including global cognitive function, memory (long-term verbal recall, long-term verbal recognition, long-term visual recall, short-term spatial recall, and short-term verbal recall), executive function (general, fluid reasoning, generativity, shifting, inhibition, and updating), language, processing speed/complex attention/working memory, visuospatial/constructional ability, and psychomotor ability. The cognitive difference between the groups of patients was measured as a standardized mean difference (SMD, Cohen's d). PD-RBD patients were classified into Confirmed-RBD (definite diagnosis with polysomnography, PSG) and Probable-RBD (without PSG re-confirmation). In some domains, RBD patients could not be analyzed separately due to the exiguity of primary studies; this analysis refers to such RBD patients as "Mixed-RBD." Results: Thirty-nine studies with 6,695 PD subjects were finally included. Confirmed-RBD patients showed worse performance than those without in global cognitive function, long-term verbal recall, long-term verbal recognition, generativity, inhibition, shifting, language, and visuospatial/constructional ability; Probable-RBD, in global cognitive function and shifting; and Mixed-RBD, in long-term visual recall, short-term spatial recall, general executive function, and processing speed/complex attention/working memory. Conclusion: This meta-analysis strongly suggests a relationship between RBD, Confirmed-RBD in particular, and cognitive dysfunctions in PD patients. Early and routine screening by sensitive and targeted cognitive tasks is necessary for all PD-RBD patients because it may offer the therapeutic time window before they evolve to irreversible dementia.

18.
Front Genet ; 11: 821, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33193563

RESUMO

Variants in the DNAJC7 gene have been shown to be novel causes of amyotrophic lateral sclerosis (ALS). However, the contributions of DNAJC7 mutations in Asian ALS patients remain unclear. In this study, we screened rare pathogenic variants in the DNAJC7 gene in a cohort of 578 ALS patients from Mainland China. A novel, rare, putative pathogenic variant c.712A>G (p.R238G) was identified in one sporadic ALS patient. The carrier with this variant exhibited symptom onset at a relatively younger age and experienced rapid disease progression. Our results expand the pathogenic variant spectrum of DNAJC7 and indicate that variants in the DNAJC7 gene may also contribute to ALS in the Chinese population.

20.
Artigo em Inglês | MEDLINE | ID: mdl-33185019

RESUMO

OBJECTIVE: Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. A significant overlap in clinical features, epidemiology, imaging, and pathology suggests that PD and ET may also share common genetic risk factors. Previous studies have only assessed a limited number of ET-associated genes in PD patients and vice versa. Consequently, the genetic association between PD and ET remains incompletely characterized. In this study, we systematically investigated a potential association between rare coding variants in ET-associated genes and PD, in a relatively large Chinese population cohort. METHODS: To investigate the genetic association between ET and PD, we performed the sequence kernel association testing (SKAT-O) to explore the variant burden of 33 ET-associated genes, using whole-exome sequencing (WES) data from 1494 early-onset PD (EOPD) patients and 1357 control subjects from mainland China. RESULTS: We report that rare loss-of-function and damaging missense variants of TNEM4 are suggestively associated with EOPD (P = 0.026), damaging missense variants of TNEM4 alone are also suggestively associated with EOPD (P = 0.032). No other rare damaging variants in ET-related genes were significantly associated with EOPD. INTERPRETATION: This is the first systematic analysis of ET-associated genes in EOPD. The suggestive association between TNEM4 and EOPD provides new evidence for a genetic link between ET and PD.

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