Distinct patterns of electrophysiologic-neuroimaging correlations between Parkinson's disease and multiple system atrophy.

Due to a high degree of symptom overlap in the early stages, with movement disorders predominating, Parkinson's disease (PD) and multiple system atrophy (MSA) may exhibit a similar decline in motor areas, yet they differ in their spread throughout the brain, ultimately resulting in two distinct diseases. Drawing upon neuroimaging analyses and altered motor cortex excitability, potential diffusion mechanisms were delved into, and comparisons of correlations across distinct disease groups were conducted in a bid to uncover significant pathological disparities. We recruited thirty-five PD, thirty-seven MSA, and twenty-eight matched controls to conduct clinical assessments, electromyographic recording, and magnetic resonance imaging scanning during the "on medication" state. Patients with neurodegeneration displayed a widespread decrease in electrophysiology in bilateral M1. Brain function in early PD was still in the self-compensatory phase and there was no significant change. MSA patients demonstrated an increase in intra-hemispheric function coupled with a decrease in diffusivity, indicating a reduction in the spread of neural signals. The level of resting motor threshold in healthy aged showed broad correlations with both clinical manifestations and brain circuits related to left M1, which was absent in disease states. Besides, ICF exhibited distinct correlations with functional connections between right M1 and left middle temporal gyrus in all groups. The present study identified subtle differences in the functioning of PD and MSA related to bilateral M1. By combining clinical information, cortical excitability, and neuroimaging intuitively, we attempt to bring light on the potential mechanisms that may underlie the development of neurodegenerative disease.

A novel compound alleviates oxidative stress via PKA/CREB1-mediated DJ-1 upregulation.

Oxidative stress is one of the major culprits causing dopaminergic neuron loss in Parkinson's disease (PD). DJ-1 is a protein with multiple actions against oxidative stress, apoptosis, neuroinflammation, etc. DJ-1 expression is decreased in sporadic PD, therefore increasing DJ-1 expression might be beneficial in PD treatment. However, drugs known to upregulate DJ-1 are still lacking. In this study, we identified a novel DJ-1-elevating compound called ChemJ through luciferase assay-based high-throughput compound screening in SH-SY5Y cells and confirmed that ChemJ upregulated DJ-1 in SH-SY5Y cell line and primary cortical neurons. DJ-1 upregulation by ChemJ alleviated MPP+-induced oxidative stress. In exploring the underlying mechanisms, we found that the transcription factor CREB1 bound to DJ-1 promoter and positively regulated its expression under both unstressed and 1-methyl-4-phenylpyridinium-induced oxidative stress conditions and that ChemJ promoted DJ-1 expression via activating PKA/CREB1 pathway in SH-SY5Y cells. Our results demonstrated that ChemJ alleviated the MPP+-induced oxidative stress through a PKA/CREB1-mediated regulation of DJ-1 expression, thus offering a novel and promising avenue for PD treatment.

Overexpression of alpha synuclein disrupts APP and Endolysosomal axonal trafficking in a mouse model of synucleinopathy.

Mutations or triplication of the alpha synuclein (ASYN) gene contribute to synucleinopathies including Parkinson's disease (PD), Dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Recent evidence suggests that ASYN also plays an important role in amyloid-induced neurotoxicity, although the mechanism(s) remains unknown. One hypothesis is that accumulation of ASYN alters endolysosomal pathways to impact axonal trafficking and processing of the amyloid precursor protein (APP). To define an axonal function for ASYN, we used a transgenic mouse model of synucleinopathy that expresses a GFP-human ASYN (GFP-hASYN) transgene and an ASYN knockout (ASYN-/-) mouse model. Our results demonstrate that expression of GFP-hASYN in primary neurons derived from a transgenic mouse impaired axonal trafficking and processing of APP. In addition, axonal transport of BACE1, Rab5, Rab7, lysosomes and mitochondria were also reduced in these neurons. Interestingly, axonal transport of these organelles was also affected in ASYN-/- neurons, suggesting that ASYN plays an important role in maintaining normal axonal transport function. Therefore, selective impairment of trafficking and processing of APP by ASYN may act as a potential mechanism to induce pathological features of Alzheimer's disease (AD) in PD patients.

Optimizing Deep Brain Stimulation in Essential Tremor: A Randomized Controlled Trial for Target Consideration.

BACKGROUND AND OBJECTIVES: The thalamic ventral intermediate nucleus (VIM) is a well-established target for deep brain stimulation (DBS) in the treatment of essential tremor (ET). Increasing data indicate that the posterior subthalamic area (PSA) may be superior, but high-level evidence is limited. We aimed at further comparing the intraindividual efficacy and side effect profile of PSA vs VIM DBS in ET. METHODS: In this randomized, double-blind, crossover trial, 4-contact DBS leads were bilaterally implanted with single-trajectory covering the VIM and PSA. Patients were randomized postsurgery to 2 groups, receiving VIM stimulation (4-7 months) and then PSA stimulation (8-11 months) or vice versa. The primary end point was the difference in improvement from baseline to the end of the VIM vs PSA DBS period in the total score of the Fahn-Tolosa-Marin Tremor Rating Scale (FTM-TRS). RESULTS: Ten patients with medically refractory ET were enrolled, and 9 completed the study. The difference between reduction of FTM-TRS total score in the PSA vs VIM DBS period was -7.4 (95% CI: -28.5 to 13.7, P = .328). Clinical benefit was achieved at significantly lower stimulation intensity under PSA DBS. Furthermore, PSA DBS provided greater improvement in head tremor subscore of FTM-TRS (PSA vs VIM: -2.2, P = .020) and disease-specific quality of life (PSA vs VIM: -13.8, P = .046) and induced fewer speech (Dysphonia Severity Index score: P = .043; diadochokinetic rate: P = .007; VDI score: P = .005) and gait disturbances compared with VIM DBS. Seven patients remained with PSA DBS after the crossover phase. CONCLUSION: Our study confirms that PSA-DBS is comparable with VIM-DBS in suppressing tremors, superior in improving disease-specific quality of life, and possibly more effective in reducing head tremor.

The genomic and epigenetic footprint of local adaptation to variable climates in kiwifruit.

A full understanding of adaptive genetic variation at the genomic level will help address questions of how organisms adapt to diverse climates. Actinidia eriantha is a shade-tolerant species, widely distributed in the southern tropical region of China, occurring in spatially heterogeneous environments. In the present study we combined population genomic, epigenomic, and environmental association analyses to infer population genetic structure and positive selection across a climatic gradient, and to assess genomic offset to climatic change for A. eriantha. The population structure is strongly shaped by geography and influenced by restricted gene flow resulting from isolation by distance due to habitat fragmentation. In total, we identified 102 outlier loci and annotated 455 candidate genes associated with the genomic basis of climate adaptation, which were enriched in functional categories related to development processes and stress response; both temperature and precipitation are important factors driving adaptive variation. In addition to single-nucleotide polymorphisms (SNPs), a total of 27 single-methylation variants (SMVs) had significant correlation with at least one of four climatic variables and 16 SMVs were located in or adjacent to genes, several of which were predicted to be involved in plant response to abiotic or biotic stress. Gradient forest analysis indicated that the central/east populations were predicted to be at higher risk of future population maladaptation under climate change. Our results demonstrate that local climate factors impose strong selection pressures and lead to local adaptation. Such information adds to our understanding of adaptive mechanisms to variable climates revealed by both population genome and epigenome analysis.

Regulation of Hsa-miR-4639-5p expression and its potential role in the pathogenesis of Parkinson's disease.

Decreased DJ-1 protein impairs antioxidative activity of neurons and plays an important role in the occurrence of Parkinson's disease (PD). We have previously identified hsa-miR-4639-5p as the post-transcriptional regulator of DJ-1. Increased expression of hsa-miR-4639-5p reduced DJ-1 level and increased oxidative stress leading to neuronal death. Therefore, understanding the detailed mechanisms by which hsa-miR-4639-5p expression is regulated will not only facilitate diagnosis but also inform the pathogenesis of PD. We examined hsa-miR-4639-5 in either the plasma or exosomes derived from the central nervous system (CNS) neurons of PD patients and healthy controls. We showed that CNS-derived exosomes gave rise to the increased plasma hsa-miR-4639-5p in PD patients, pointing to hsa-miR-4639-5p dysregulation in the brain of PD patients. Using a dual-luciferase assay and a CRISPR-Cas9 system, we identified a core promoter of hsa-miR-4639 (-560 to -275 upstream the transcriptional starting site) of the gene for myosin regulatory light chain interacting protein. A polymorphism in the core promoter (rs760632 G>A) could enhance hsa-miR-4639-5p expression and increase PD risk. Furthermore, using MethylTarget™ assay, ChIP-qPCR, and specific inhibitors, we demonstrated that hsa-miR4639-5p expression was regulated by HDAC11-mediated histone acetylation but not DNA methylation/demethylation. Taken together, our study provides evidence that hsa-miR-4639-5p is a potential diagnostic marker and therapeutic target for PD. Interventions targeting hsa-miR-4639-5p might represent a novel therapy to promote healthy aging.

Antibody-mediated autoimmune encephalitis evaluated by 18F-DPA714 PET/MRI.

SARS-CoV-2 vaccine has considered being the most effective method to prevent SARS-CoV-2 infection. The safety and effectiveness of the SARS-CoV-2 vaccine has been confirmed. However, in very rare cases, autoimmune neurological diseases may occur. In this article, we report three rare cases of autoimmune encephalitis with definite auto-antibody after SARS-CoV-2 vaccination. They all have good prognosis after treatment. In addition, we first use 18F-DPA-714 PET/MRI to evaluate microglia activation in our patients. We found that 18F-DPA-714 PET/MRI may be a powerful tool for quantitative analysis of neuroinflammation in patients of autoimmune encephalitis. Finally, although rare complications may happen after vaccination, we still consider the benefits of vaccination far outweigh the risks. People without contraindications should be vaccinated without delay to prevent infection in current outbreak situation.

Ras and Rab Interactor 3: From Cellular Mechanisms to Human Diseases.

Ras and Rab interactor 3 (RIN3) functions as a Guanine nucleotide Exchange Factor (GEF) for some members of the Rab family of small GTPase. By promoting the activation of Rab5, RIN3 plays an important role in regulating endocytosis and endocytic trafficking. In addition, RIN3 activates Ras, another small GTPase, that controls multiple signaling pathways to regulate cellular function. Increasing evidence suggests that dysregulation of RIN3 activity may contribute to the pathogenesis of several disease conditions ranging from Paget's Disease of the Bone (PDB), Alzheimer's Disease (AD), Chronic Obstructive Pulmonary Disease (COPD) and to obesity. Recent genome-wide association studies (GWAS) identified variants in the RIN3 gene to be linked with these disease conditions. Interestingly, some variants appear to be missense mutations in the functional domains of the RIN3 protein while most variants are located in the noncoding regions of the RIN3 gene, potentially altering its gene expression. However, neither the protein structure of RIN3 nor its exact function(s) (except for its GEF activity) has been fully defined. Furthermore, how the polymorphisms/variants contribute to disease pathogenesis remain to be understood. Herein, we examine, and review published studies in an attempt to provide a better understanding of the physiological function of RIN3; More importantly, we construct a framework linking the polymorphisms/variants of RIN3 to altered cell signaling and endocytic traffic, and to potential disease mechanism(s).

Upregulation of RIN3 induces endosomal dysfunction in Alzheimer's disease.

BACKGROUND: In Alzheimer's Disease (AD), about one-third of the risk genes identified by GWAS encode proteins that function predominantly in the endocytic pathways. Among them, the Ras and Rab Interactor 3(RIN3) is a guanine nucleotide exchange factor (GEF) for the Rab5 small GTPase family and has been implicated to be a risk factor for both late onset AD (LOAD) and sporadic early onset AD (sEOAD). However, how RIN3 is linked to AD pathogenesis is currently undefined. METHODS: Quantitative PCR and immunoblotting were used to measure the RIN3 expression level in mouse brain tissues and cultured basal forebrain cholinergic neuron (BFCNs). Immunostaining was used to define subcellular localization of RIN3 and to visualize endosomal changes in cultured primary BFCNs and PC12 cells. Recombinant flag-tagged RIN3 protein was purified from HEK293T cells and was used to define RIN3-interactomes by mass spectrometry. RIN3-interacting partners were validated by co-immunoprecipitation, immunofluorescence and yeast two hybrid assays. Live imaging of primary neurons was used to examine axonal transport of amyloid precursor protein (APP) and ß-secretase 1 (BACE1). Immunoblotting was used to detect protein expression, processing of APP and phosphorylated forms of Tau. RESULTS: We have shown that RIN3 mRNA level was significantly increased in the hippocampus and cortex of APP/PS1 mouse brain. Basal forebrain cholinergic neurons (BFCNs) cultured from E18 APP/PS1 mouse embryos also showed increased RIN3 expression accompanied by early endosome enlargement. In addition, via its proline rich domain, RIN3 recruited BIN1(bridging integrator 1) and CD2AP (CD2 associated protein), two other AD risk factors, to early endosomes. Interestingly, overexpression of RIN3 or CD2AP promoted APP cleavage to increase its carboxyl terminal fragments (CTFs) in PC12 cells. Upregulation of RIN3 or the neuronal isoform of BIN1 increased phosphorylated Tau level. Therefore, upregulation of RIN3 expression promoted accumulation of APP CTFs and increased phosphorylated Tau. These effects by RIN3 was rescued by the expression of a dominant negative Rab5 (Rab5S34N) construct. Our study has thus pointed to that RIN3 acts through Rab5 to impact endosomal trafficking and signaling. CONCLUSION: RIN3 is significantly upregulated and correlated with endosomal dysfunction in APP/PS1 mouse. Through interacting with BIN1 and CD2AP, increased RIN3 expression alters axonal trafficking and procession of APP. Together with our previous studies, our current work has thus provided important insights into the role of RIN3 in regulating endosomal signaling and trafficking.

The complete chloroplast genome sequence of Actinidia eriantha.

The complete chloroplast (cp) genome sequence of Actinidia eriantha was sequenced and assembled using Illumina paired-end data. The cp genome from A. eriantha is 156,964 bp in length, composed of a pair of 23,892 bp inverted repeat regions (IR) separated by a large single copy region (LSC) of 88,639 bp and a small single copy region (SSC) of 20,541 bp. The cp genome contained 113 unique genes, including 79 protein-coding genes, 30 tRNA genes, and four ribosomal RNA genes. The phylogenetic position of A. eriantha based the cp genome data was sister to the group A. rufa, A. deliciosa, and A. chinensis.

Corrigendum: Association of Two Polymorphisms in CCL2 With Parkinson's Disease: A Case-Control Study.

[This corrects the article DOI: 10.3389/fneur.2019.00035.].

Association of Two Polymorphisms in CCL2 With Parkinson's Disease: A Case-Control Study.

Background: Parkinson's disease (PD) is the most common neurodegenerative movement disorder that is known to be related to neuro-inflammation. Chemokines participate in this process usually through upregulation of expression levels, which are closely related to the polymorphisms in their genes. Recent studies have further revealed the association between these polymorphisms and the risk of PD in multiple populations, but not the Chinese Han population. Methods:The promoter region of CCL2 was sequenced in 411 PD patients and 422 gender-age matched control from a Chinese Han population using PCR-RFLP method. Their genotype frequencies were analyzed statistically. Dual-luciferase reporter assays were conducted in neuroblastoma cells to assess the promoter transcriptional activity of the rs1024611 variants (T>C) and the GRCh38.p12chr17:34252593 G>C alleles in CCL2. Results:We found that the frequency of the CCL2 genotype of rs1024611 was significantly different between the PD and control groups (p = 0.021), while the C allele was associated with a significantly increased risk in the PD group (p = 0.004). Moreover, C allele of this newly identified alteration in CCL2 (GRCh38.p12chr17:34252593 G>C) was also found to be associated with an increased risk of PD (P genotype = 0.006, P allele = 0.006). Dual-luciferase reporter assay results indicated that rs1024611 C allele and GRCh38.p12chr17:.34252593 C allele increased the transcriptional activity of the CCL2 promoter. Conclusions: We, for the first time, report a risk polymorphism (rs1024611) and a new locus (GRCh38.p12chr17:.34252593 G>C) on CCL2, both of which are suggested as risk factors for PD in a Chinese Han population.

Deep brain stimulation of the globus pallidus internus versus the subthalamic nucleus in isolated dystonia.

OBJECTIVE: Surgical procedures involving deep brain stimulation (DBS) of the globus pallidus internus (GPi) or subthalamic nucleus (STN) are well-established treatments for isolated dystonia. However, selection of the best stimulation target remains a matter of debate. The authors' objective was to compare the effectiveness of DBS of the GPi and the STN in patients with isolated dystonia. METHODS: In this matched retrospective cohort study, the authors searched an institutional database for data on all patients with isolated dystonia who had undergone bilateral implantation of DBS electrodes in either the GPi or STN in the period from January 30, 2014, to June 30, 2017. Standardized assessments of dystonia and health-related quality of life using the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) and SF-36 were conducted before and at 1, 6, and 12 months after surgery. No patients were lost to the 6-month follow-up; 5 patients were lost to the 12-month follow-up. RESULTS: Both GPi (14 patients) and STN (16 patients) stimulation produced significant improvement in dystonia and quality of life in all 30 patients found in the database search. At the 1-month follow-up, however, the percentage improvement in the BFMDRS total movement score was significantly (p = 0.01) larger after STN DBS (64%) than after GPi DBS (48%). At the 12-month follow-up, the percentage improvement in the axis subscore was significantly (p = 0.03) larger after GPi DBS (93%) than after STN DBS (83%). Also, the total amount of electrical energy delivered was significantly (p = 0.008) lower with STN DBS than with GPi DBS (124 ± 52 vs 192 ± 65 µJ, respectively). CONCLUSIONS: The GPi and STN are both effective targets in alleviating dystonia and improving quality of life. However, GPi stimulation may be better for patients with axial symptoms. Moreover, STN stimulation may produce a larger clinical response within 1 month after surgery and may have a potential economic advantage in terms of lower battery consumption.

Lack of Association Between DJ-1 Gene Promoter Polymorphism and the Risk of Parkinson's Disease.

Low DJ-1 protein level caused by DJ-1 gene mutation leads to autosomal recessive Parkinson's disease (PD) due to impaired antioxidative activity. In sporadic PD patients, although mutations were rarely found, lower DJ-1 protein level was also reported. Dysregulation of DJ-1 gene expression might contribute to low DJ-1 protein level. Since the promoter is the most important element to initiate gene expression, whether polymorphisms in the DJ-1 promoter result in the dysregulation of gene expression, thus leading to low protein level and causing PD, is worth exploring. The DJ-1 promoter region was sequenced in a Chinese cohort to evaluate possible links between DJ-1 promoter polymorphisms, PD risk and clinical phenotypes. Dual-luciferase reporter assay was conducted to evaluate the influence of promoter polymorphisms on DJ-1 transcriptional activity. Related information in an existing genome-wide association studies (GWAS) database were looked up, meta-analysis of the present study and other previous reports was conducted, and expression quantitative trait loci (eQTL) analysis was performed to further explore the association. Three single nucleotide polymorphisms (SNPs) (rs17523802, rs226249, and rs35675666) and one 18 bp deletion (rs200968609) were observed in our cohort. However, there was no significant association between the four detected genetic variations and the risk of PD either in allelic or genotype model, in single-point analysis or haplotype analysis. This was supported by the meta-analysis of this study and previous reports as well as that of GWAS database PDGene. Dual luciferase reporter assay suggested these promoter polymorphisms had no influence on DJ-1 transcriptive activity, which is consistent with the eQTL analysis results using the data from GTEx database. Thus, DJ-1 promoter polymorphisms may play little role in the dysregulation of DJ-1 expression and PD susceptibility in sporadic PD.

BMP6 Regulates Proliferation and Apoptosis of Human Sertoli Cells Via Smad2/3 and Cyclin D1 Pathway and DACH1 and TFAP2A Activation.

Sertoli cells are essential for regulating normal spermatogenesis. However, the mechanisms underlying human Sertoli cell development remain largely elusive. Here we examined the function and signaling pathways of BMP6 in regulating human Sertoli cells. RT-PCR, immunocytochemistry and Western blots revealed that BMP6 and its multiple receptors were expressed in human Sertoli cells. CCK-8 and EDU assays showed that BMP6 promoted the proliferation of Sertoli cells. Conversely, BMP6 siRNAs inhibited the division of these cells. Annexin V/PI assay indicated that BMP6 reduced the apoptosis in human Sertoli cells, whereas BMP6 knockdown assumed reverse effects. BMP6 enhanced the expression levels of ZO1, SCF, GDNF and AR in human Sertoli cells, and ELISA assay showed an increase of SCF by BMP6 and a reduction by BMP6 siRNAs. Notably, Smad2/3 phosphorylation and cyclin D1 were enhanced by BMP6 and decreased by BMP6 siRNAs in human Sertoli cells. The levels of DACH1 and TFAP2A were increased by BMP6 and reduced by BMP6 siRNAs, and the growth of human Sertoli cells was inhibited by these siRNAs. Collectively, these results suggest that BMP6 regulates the proliferation and apoptosis of human Sertoli cells via activating the Smad2/3/cyclin D1 and DACH1 and TFAP2A pathway.

The Function and Regulation of BMP6 in Various Kinds of Stem Cells.

Stem cells, by definition, are the primitive cells that have the potential of both self-renewal and differentiation into a number of mature and functional cells, and thus they have great applications in cell therapy and tissue engineering for regenerative medicine. Bone morphogenetic protein 6 (BMP6) belongs to transforming growth factor ß(TGF-ß) superfamily. The fate determinations of stem cells require complex regulatory networks that involve BMP6 signaling pathway. Recent studies have demonstrated that BMP6 plays crucial roles in controlling the self-renewal and differentiation of stem cells. In this review, we address the expression, function and regulation of BMP6 in various kinds of stem cells, with focus on mesenchymal stem cells (MSCs), germline stem cells (GSCs), hematopoietic stem cells (HSCs), and neural stem cells (NSCs). Notably, there are distinct effects of BMP6 on promoting self-renewal and differentiation of these stem cells. We also discuss the involement of BMP6 in diseases, including leukemia, astrocytic glioma, and Alzheimer's disease, and the therapy of these diseases via gene targeting. We further highlight certain issues for further investigation on the regulation and function of BMP6 in stem cells. Significantly, a thorough understanding of BMP6 regulation on a variety of adult stem cells could make them feasible for applications in both regenerative and reproductive medicine, and it would shed novel insights into the etiology of the diseases and offer new targets for drug design to treat these disorders.