Splicing mutations of GALC in adult patient with adult-onset Krabbe disease: case report and review of literature.

Krabbe disease (KD) is classed as the lysosomal storage disease with mutations in the galactosylceramidase (GALC) gene, and commonly showed as autosomal recessive pattern with 30-kb deletion in infantile subtype. In this case, we report a 39-years adult-onset KD (AOKD) patient with multiple sclerosis-like symptoms and neuroimaging changes. She carries the heterozygous mutations in GALC included a missense mutation of c.1901T>C from her mother, and a splicing mutation of c.908+5G>A from her father. The splicing mutations in KD are reviewed and confirmed that c.908+5G>A is a novel splicing mutation in AOKD.

Parkinson's disease in a patient with GBA and LRRK2 covariants after acute hypoxic insult: a case report.

BACKGROUND: The glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 (LRRK2) genes are associated with the risk of sporadic Parkinson's disease (PD). As an environmental factor, hypoxic insults may impair dopamine neurons in the substantia nigra and exacerbate PD symptoms. However, covariants of GBA and LRRK2 combined with hypoxic insults in clinical cases of Parkinsonism have not yet been reported. CASE PRESENTATION: A 69-year-old male patient with PD and his relatives were clinically characterized and sequenced using the whole-exome technique. A novel covariant, c.1448 T > C (p. L483P, rs421016) on GBA and c.691 T > C (p. S231P, rs201332859) on LRRK2 were identified in this patient who first developed bradykinesia and rigidity in the neck at one month after an acute hypoxic insult during mountaineering. The patient presented with a mask-like face, festinating gait, asymmetric bradykinesia, and moderate rigidity. These symptoms were treated with levodopa and pramipexole, resulting in a 65% improvement in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score. These parkinsonian symptoms persisted and developed with hallucinations, constipation, and rapid eye movement sleep behavior disorder. After 4 years, the patient exhibited a wearing-off phenomenon and died from pulmonary infection 8 years after disease onset. His parents, wife, and siblings were not diagnosed with PD, and his son carried p. L483P without Parkinsonism-like symptoms. CONCLUSIONS: This is a case report of PD after hypoxic insult in a patient carrying a covariant of GBA and LRRK2. This study may help us understand the interaction between genetic and environmental factors in clinical PD.

Association of ADAM10 gene variants with sporadic Parkinson's disease in Chinese Han population.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide. Genetic factors play important roles in PD risk. rs653765 and rs514049 of ADAM10 were reported to be associated with Alzheimer's disease (AD) in Caucasian population; however, the association of the two variants with PD in Chinese Han population remains unknown. The present investigation aimed to explore the possible association of ADAM10 variants with PD in Chinese Han population. METHODS: We enrolled 565 PD patients and 518 healthy controls to conduct a case-control study. DNA samples were extracted from peripheral blood leukocytes, and the genotypes were determined by utilization of MassARRAY platform. Plasma levels were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: We found CC genotype of rs514049 was associated with an increased risk of PD (OR (95% CI) = 3.776 (1.127-11.217), p = 0.018). The C allele frequency of rs514049 was significantly higher in PD group (OR (95% CI) = 1.328 (1.031-1.709), p = 0.028), especially in male subgroup (OR (95% CI) = 1.484 (1.053-2.092), p = 0.024). However, there was no significant difference in the genotype or allele frequencies for rs653765 within the groups. Plasma levels were significantly decreased in PD patients compared with controls (p < 0.001). CONCLUSIONS: Our data suggested that C allele of rs514049 in ADAM10 may increase the risk of PD in Chinese Han population, especially in males. The decreased plasma levels are probably involved in PD development.

Association of CLU gene polymorphism with Parkinson's disease in the Chinese Han population.

BACKGROUND: Clusterin (CLU) plays important role in the pathology of neurodegenerative disorders. Recently, a genetic variant of CLU rs9331896 has been reported as a risk estimate for Alzheimer's disease (AD). However, the association between this variant and the risk of Parkinson's disease (PD) in the Chinese Han population remains elusive. METHODS: We sequenced CLU rs9331896 in 353 PD patients and 326 healthy-matched individuals of the Chinese Han population. The genotypes of rs9331896 were analyzed using MassArray (Agena Bioscience, San Diego, CA, USA) in accordance with the manufacturer's instructions. The distribution of genotypes and allelic frequencies was analyzed by a chi-squared test. Additionally, the expression of CLU protein in plasma was evaluated by an enzyme-linked immunosorbent assay and analysed with a t-test. RESULTS: The TT genotype in rs9331896 in a recessive model was found to be associated with the increased risk of PD (odds ratio = 1.408, 95% confidence interval = 1.034-1.916, p = 0.029). Subgroup analysis indicated that TT genotype carriers showed a significantly higher risk in male PD patients compared to male healthy controls (odds ratio = 1.611, 95% confidence interval = 1.046-2.483, p = 0.030). In addition, CLU levels in the plasma of PD patients were significantly higher than controls (p = 0.024). CONCLUSIONS: The CLU-rs9331896-TT genotype was a risk factor for PD, particularly in males. PD patients also expressed a high level of CLU in plasma.

Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections.

Seizures are common in humans with various etiologies ranging from congenital aberrations to acute injuries that alter the normal balance of brain excitation and inhibition. A notable consequence of seizures is the induction of aberrant neurogenesis and increased immature neuronal projections. However, regulatory mechanisms governing these features during epilepsy development are not fully understood. Recent studies show that microglia, the brain's resident immune cell, contribute to normal neurogenesis and regulate seizure phenotypes. However, the role of microglia in aberrant neurogenic seizure contexts has not been adequately investigated. To address this question, we coupled the intracerebroventricular kainic acid model with current pharmacogenetic approaches to eliminate microglia in male mice. We show that microglia promote seizure-induced neurogenesis and subsequent seizure-induced immature neuronal projections above and below the pyramidal neurons between the DG and the CA3 regions. Furthermore, we identify microglial P2Y12 receptors (P2Y12R) as a participant in this neurogenic process. Together, our results implicate microglial P2Y12R signaling in epileptogenesis and provide further evidence for targeting microglia in general and microglial P2Y12R in specific to ameliorate proepileptogenic processes.SIGNIFICANCE STATEMENT Epileptogenesis is a process by which the brain develops epilepsy. Several processes have been identified that confer the brain with such epileptic characteristics, including aberrant neurogenesis and increased immature neuronal projections. Understanding the mechanisms that promote such changes is critical in developing therapies to adequately restrain epileptogenesis. We investigated the role of purinergic P2Y12 receptors selectively expressed by microglia, the resident brain immune cells. We report, for the first time, that microglia in general and microglial P2Y12 receptors in specific promote both aberrant neurogenesis and increased immature neuronal projections. These results indicate that microglia enhance epileptogenesis by promoting these processes and suggest that targeting this immune axis could be a novel therapeutic strategy in the clinic.

The outcome and burden of Chinese patients with neurodegenerative diseases: A 10-year clinical feature study.

BACKGROUND: As the Chinese population continues to age, the incidence of neurodegenerative diseases (NDDs) has increased dramatically, which results in heavy medical and economic burden for families and society. OBJECTIVE: The objective of this study was to evaluate NDDs in a southern Chinese hospital over a 10-year period and examine trends in demographics, outcome, length of stay (LOS) and cost. METHODS: Retrospective medical records of patients from January 2010 to December 2019 were collected, including 7231 patients with NDDs (as case group) and 9663 patients without any NDDs (as control group). The information of social demographic data, admission source, reasons for admission, outcomes, LOS, and cost were extracted and analysed. RESULT: The average hospitalisation age of the patients with NDDs is over 65 years (peak age 70-89 years). Compared with the control group, the case group had a longer LOS and a higher cost and the numbers of patients with NDDs increased yearly from 2010 to 2019. The LOS shortened while the cost increased. Clinical features affected LOS and cost. Patients suffering from infection, abnormal blood pressure and the imbalance of water-electrolyte homoeostasis as main reasons for admission were decreased; however, heart disease, cerebrovascular accident and mental diseases were significantly increased, the overall change trend of fracture/trauma remained stable. The rate of discharge to home care and mortality declined; discharge to other medical or community facilities increased over 10 years. CONCLUSION: The majority of NDDs patients tended to be older. During the last 10 years from 2010 to 2019, the numbers of NDDs patients increased yearly, the trend of LOS became shortening and the cost gradually increasing. The main reasons of admission and outcomes of hospital showed different trends.

Association of LAG3 genetic variation with an increased risk of PD in Chinese female population.

BACKGROUND: Emerging evidence suggests that α-synuclein (α-syn) aggregation and intercellular transmission contributes to pathogenesis of Parkinson's disease (PD) and the toxic fibrillary α-syn binds lymphocyte-activation gene 3 (LAG3) receptor that mediates α-syn transmission. The deletion of LAG3 in animal models was shown to limit α-syn spreading and alleviate the pathological changes of dopaminergic neurons and animal behavioral deficits induced by α-syn aggregation. However, little is known about the genetic association of LAG3 variation with human PD development. OBJECTIVE: Here we investigated LAG3 single nucleotide polymorphisms (SNPs) and examined the levels of soluble LAG3 (sLAG3) of CSF and serum from Chinese PD patients. METHODS: We enrolled 646 PD patients and 536 healthy controls to conduct a case-control study. All the participants were genotyped using Sequenom iPLEX Assay and the partial cerebrospinal fluid (CSF) and serum samples were assessed by Meso Scale Discovery electrochemiluminescence (MSD-ECL) immunoassay to measure sLAG3 concentration. RESULTS: As a result, distributions of rs1922452-AA (1.975, 95% confidence interval (CI) 1.311-2.888, p = 0.001) and rs951818-CC (OR = 2.03, 95% CI 1.369-3.010, p = 0.001) genotype frequencies were found higher in the female PD patients than controls, respectively, and a strong linkage disequilibrium (LD) was calculated on the variants. The level of sLAG3 in CSF of PD patients was found to significantly differ from that of controls (51.56 ± 15.05 pg/ml vs 88.49 ± 62.96 pg/ml, p < 0.0001). Meanwhile, the concentration of α-synuclein in CSF of patients was significantly lower than that of controls (939.9 ± 2900 pg/ml vs 2476 ± 4403 pg/ml, p < 0.0001) and the level of sLAG3 was detected to be positive correlation with that of α-synuclein in the control group (r = 0.597, p = 0.0042), but not in PD group (r = 0.111, p = 0.408). CONCLUSION: In summary, our data suggested that LAG3 SNPs increase the PD risk of Chinese female population and the sLAG3 may be a potential biomarker predicted for PD development.

Wnt1 Promotes EAAT2 Expression and Mediates the Protective Effects of Astrocytes on Dopaminergic Cells in Parkinson's Disease.

Background: Wnt/ß-catenin signaling has been reported to exert cytoprotective effects in a cellular model of Parkinson's disease (PD). Glutamate excitotoxicity has been suggested to contribute to the pathogenesis of PD, and excitatory amino acid transporters (EAATs) play a predominant role in clearing excessive glutamate. EAAT2 is mainly expressed in astrocytes, which are an important source of Wnt signaling in the brain. Methods: Wnt1-overexpressing U251 astrocytes were indirectly cocultured with dopaminergic SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA). Cell toxicity was determined by cell viability and flow cytometric detection. Glutamate level in the culture medium was determined by enzyme-linked immunosorbent assay (ELISA). Western blot analysis was used to detect the expression of Wnt1, ß-catenin, and EAAT2. Immunofluorescence was used to display the expression and translocation of NF-κB p65. Results: 6-OHDA treatment significantly decreased cell viability in both U251 cells and SH-SY5Y cells, inhibited the expression of Wnt1, ß-catenin, and EAAT2 in U251 cells, and increased the glutamate level in the culture medium. Coculture with Wnt1-overexpressing U251 cells attenuated 6-OHDA-induced apoptosis in SH-SY5Y cells. Overexpression of Wnt1 decreased the glutamate level in the culture media, upregulated ß-catenin, EAAT2, and NF-κB levels, and promoted the translocation of NF-κB from the cytoplasm to the nucleus in U251 cells. Conclusion: Wnt1 promoted EAAT2 expression and mediated the cytoprotective effects of astrocytes on dopaminergic cells. NF-κB might be involved in the regulation of EAAT2 by Wnt1.

Iron promotes α-synuclein aggregation and transmission by inhibiting TFEB-mediated autophagosome-lysosome fusion.

Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of α-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl2, and α-synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over-expression. Our results demonstrated that iron promoted α-synuclein aggregation and transmission by inhibiting autophagosome-lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome-lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α-synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over-expressed, the transmission of α-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α-synuclein, and identify TFEB as not only a potential target for preventing α-synuclein transmission, but also a critical factor for iron-induced α-synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α-synuclein transmission in Parkinson's disease.

Association of IGF1 gene polymorphism with Parkinson's disease in a Han Chinese population.

BACKGROUND: Accumulating evidence suggests that insulin-like growth factor 1 (IGF1) plays an important role in Parkinson's disease (PD) pathogenesis. However, it is not clear whether IGF1 polymorphism contributes to PD risk. METHODS: We performed a case-control study in a Han Chinese population that included 512 sporadic PD cases and 535 matched controls. All participants were genotyped for rs972936 using the Sequenom MassARRAY iPLEX platform. Serum IGF1 levels of 61 de novo, drug-naïve PD patients and 55 age- and sex-matched controls were also measured using an enzyme-linked immunosorbent assay. RESULTS: Genotype frequency of rs972936-CC was significantly associated with an increased PD risk (p = 0.009), especially in males (p = 0.024) and late-onset patients (p = 0.013). Serum IGF1 levels were significantly increased in de novo, drug-naïve PD patients compared to controls (p = 0.036), although they were not correlated with motor dysfunction in PD patients (p = 0.220). CONCLUSIONS: The present study shows that rs972936 polymorphism may increase susceptibility to PD, especially in males and late-onset patients. Furthermore, high serum IGF1 levels may be a potential diagnostic biomarker for PD in the Han Chinese population, although they do not correlate with a more severe motor dysfunction.

Association of DNMT3b gene variants with sporadic Parkinson's disease in a Chinese Han population.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Epigenetic modifications, specifically DNA methylation, have been implicated in the development of this disease. Genetic variants of DNA methyltransferase 3b (DNMT3b), one of the most important DNA methyltransferases, were shown to be associated with PD in a Brazilian population. However, it is unclear whether genetic variants of DNMT3b increase the risk of PD in the Chinese Han people. The present study aimed to investigate the association of the DNMT3b variants rs2424913, rs998382 and rs2424932 with PD in a Chinese Han population. METHODS: We studied 487 Chinese Han patients with sporadic PD and 485 healthy age-, sex- and ethnicity-matched controls. DNA was extracted from peripheral blood leukocytes and the individual genotypes were determined using the SNaPshot method. RESULTS: We found that the rs2424932 and rs998382 variants were significantly associated with an increased risk of PD compared to the controls [rs2424932: odds ratio (OR) = 1.632, 95% confidence interval (CI) = 1.108-2.406, p = 0.013; rs998382: OR = 1.612, 95% CI = 1.103-2.382, p = 0.014]. Subgroup analysis suggested that female patients carrying the rs2424932 or rs998382 variants were more likely to develop PD than female controls (rs2424932: OR = 3.863, 95% CI = 2.004-7.445, p < 0.001; rs998382: OR = 3.679, 95% CI = 1.943-6.964, p < 0.001). Haplotype analysis indicated that the three variants comprised one block and that the Trs2424913 -Crs998382 -A rs2424932 haplotype was correlated with an increased risk of PD (p = 0.0046), especially for Chinese Han females (p < 0.0001). CONCLUSIONS: The results of the present study strongly suggest that DNMT3b variants are associated with PD in the Chinese Han people, especially females.

[Clinical analysis of subpopulation of peripheral T and B lymphocytes in Chinese Parkinson's disease patients].

OBJECTIVE: To explore the variations of subpopulation of peripheral lymphocytes in Parkinson's disease (PD) and locate its potential biomarkers for clinical evaluations. METHODS: The methods of direct immunostaining and flow cytometry were employed to test the percentages of CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD19(+) lymphocytes in blood samples of 77 PD patients and 82 healthy controls. And the percentages of CD3(+)CD4(+) and CD3(+)CD8(+) lymphocytes and the parameters of patients and health controls were analyzed. RESULTS: Compared to controls, the percentages of CD3(+), CD3(+)CD4(+) lymphocytes significantly decreased in PD patients ((62 ± 12)% vs (66 ± 9) %, P = 0.04; (35 ± 9) % vs (38 ± 7) %, P = 0.02), especially in males ((66 ± 9)% vs (61 ± 13) %, P = 0.02; (38 ± 10) % vs (33 ± 9) %, P = 0.01)) . Furthermore, the percentage of CD3(+) lymphocytes had a positive correlation with the course of PD in male patients (r = 0.329, P = 0.013, ß = 1.423). And a negative correlation existed between the percentage of CD3(+)CD4(+) lymphocytes and the course of PD and there was a positive correlation with NMSS scale in female PD patients (r = -0.309, P = 0.045, ß = -0.354; r = 0.370, P = 0.020, ß = 0.486). CONCLUSION: The variants in subpopulation of peripheral lymphocytes in PD patients may serve as a potential biomarker for diagnosing PD and predicting its clinical course.

Lipid Metabolism Disorder in Cerebrospinal Fluid Related to Parkinson's Disease.

BACKGROUND: Abnormal accumulation of lipids is found in dopamine neurons and resident microglia in the substantia nigra of patients with Parkinson's disease (PD). The accumulation of lipids is an important risk factor for PD. Previous studies have mainly focussed on lipid metabolism in peripheral blood, but little attention has been given to cerebrospinal fluid (CSF). We drew the lipidomic signature in CSF from PD patients and evaluated the role of lipids in CSF as biomarkers for PD diagnosis. METHODS: Based on lipidomic approaches, we investigated and compared lipid metabolism in CSF from PD patients and healthy controls without dyslipidaemia in peripheral blood and explored the relationship of lipids between CSF and serum by Pearson correlation analysis. RESULTS: A total of 231 lipid species were detected and classified into 13 families in the CSF. The lipid families, including phosphatidylcholine (PC), sphingomyelin (SM) and cholesterol ester (CE), had significantly increased expression compared with the control. Hierarchical clustering was performed to distinguish PD patients based on the significantly changed expression of 34 lipid species. Unsupervised and supervised methods were used to refine this classification. A total of 12 lipid species, including 3-hydroxy-dodecanoyl-carnitine, Cer(d18:1/24:1), CE(20:4), CE(22:6), PC(14:0/18:2), PC(O-18:3/20:2), PC(O-20:2/24:3), SM(d18:0/16:0), SM(d18:2/14:0), SM(d18:2/24:1), SM(d18:1/20:1) and SM(d18:1/12:0), were selected to draw the lipidomic signature of PD. Correlation analysis was performed and showed that the CE family and CE (22:6) in CSF had a positive association with total cholesterol in the peripheral blood from PD patients but not from healthy controls. CONCLUSIONS: Our results revealed that the lipidomic signature in CSF may be considered a potential biomarker for PD diagnosis, and increased CE, PC and SM in CSF may reveal pathological changes in PD patients, such as blood-brain barrier leakage.

A case of congenital afibrinogenemia with multiple thrombotic and hemorrhagic disorders.

This is a case of congenital afibrinogenemia with multiple thrombotic and hemorrhagic events. His fibrinogen concentration was negatively correlated with thrombin time and prothrombin time and abnormally negatively correlated with plasma D-dimer levels. The individualized standard for fibrinogen concentration may help to balance thrombotic and hemorrhagic events for this disease.

CHCHD2 maintains mitochondrial contact site and cristae organizing system stability and protects against mitochondrial dysfunction in an experimental model of Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's dementia. Mitochondrial dysfunction is involved in the pathology of PD. Coiled-coil-helix-coiled-coil-helix domain-containing 2 (CHCHD2) was identified as associated with autosomal dominant PD. However, the mechanism of CHCHD2 in PD remains unclear. METHODS: Short hairpin RNA (ShRNA)-mediated CHCHD2 knockdown or lentivirus-mediated CHCHD2 overexpression was performed to investigate the impact of CHCHD2 on mitochondrial morphology and function in neuronal tumor cell lines represented with human neuroblastoma (SHSY5Y) and HeLa cells. Blue-native polyacrylamide gel electrophoresis (PAGE) and two-dimensional sodium dodecyl sulfate-PAGE analysis were used to illustrate the role of CHCHD2 in mitochondrial contact site and cristae organizing system (MICOS). Co-immunoprecipitation and immunoblotting were used to address the interaction between CHCHD2 and Mic10. Serotype injection of adeno-associated vector-mediated CHCHD2 and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were used to examine the influence of CHCHD2 in vivo. RESULTS: We found that the overexpression of CHCHD2 can protect against methyl-4-phenylpyridinium (MPP+)-induced mitochondrial dysfunction and inhibit the loss of dopaminergic neurons in the MPTP-induced mouse model. Furthermore, we identified that CHCHD2 interacted with Mic10, and overexpression of CHCHD2 can protect against MPP+-induced MICOS impairment, while knockdown of CHCHD2 impaired the stability of MICOS. CONCLUSION: This study indicated that CHCHD2 could interact with Mic10 and maintain the stability of the MICOS complex, which contributes to protecting mitochondrial function in PD.

Chaperone-mediated Autophagy Regulates Cell Growth by Targeting SMAD3 in Glioma.

Previous studies suggest that the reduction of SMAD3 (mothers against decapentaplegic homolog 3) has a great impact on tumor development, but its exact pathological function remains unclear. In this study, we found that the protein level of SMAD3 was greatly reduced in human-grade IV glioblastoma tissues, in which LAMP2A (lysosome-associated membrane protein type 2A) was significantly up-regulated. LAMP2A is a key rate-limiting protein of chaperone-mediated autophagy (CMA), a lysosome pathway of protein degradation that is activated in glioma. We carefully analyzed the amino-acid sequence of SMAD3 and found that it contained a pentapeptide motif biochemically related to KFERQ, which has been proposed to be a targeting sequence for CMA. In vitro, we confirmed that SMAD3 was degraded in either serum-free or KFERQ motif deleted condition, which was regulated by LAMP2A and interacted with HSC70 (heat shock cognate 71 kDa protein). Using isolated lysosomes, amino-acid residues 75 and 128 of SMAD3 were found to be of importance for this process, which affected the CMA pathway in which SMAD3 was involved. Similarly, down-regulating SMAD3 or up-regulating LAMP2A in cultured glioma cells enhanced their proliferation and invasion. Taken together, these results suggest that excessive activation of CMA regulates glioma cell growth by promoting the degradation of SMAD3. Therefore, targeting the SMAD3-LAMP2A-mediated CMA-lysosome pathway may be a promising approach in anti-cancer therapy.

Lipid profiles in the cerebrospinal fluid of rats with 6-hydroxydopamine-induced lesions as a model of Parkinson's disease.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disease with characteristic pathological abnormalities, including the loss of dopaminergic (DA) neurons, a dopamine-depleted striatum, and microglial activation. Lipid accumulation exhibits a close relationship with these pathologies in PD. Methods: Here, 6-hydroxydopamine (6-OHDA) was used to construct a rat model of PD, and the lipid profile in cerebrospinal fluid (CSF) obtained from model rats was analyzed using lipidomic approaches. Results: Establishment of this PD model was confirmed by apomorphine-induced rotation behaviors, loss of DA neurons, depletion of dopamine in the striatum, and microglial activation after 6-OHDA-induced lesion generation. Unsupervised and supervised methods were employed for lipid analysis. A total of 172 lipid species were identified in CSF and subsequently classified into 18 lipid families. Lipid families, including eicosanoids, triglyceride (TG), cholesterol ester (CE), and free fatty acid (FFA), and 11 lipid species exhibited significantly altered profiles 2 weeks after 6-OHDA administration, and significant changes in eicosanoids, TG, CE, CAR, and three lipid species were noted 5 weeks after 6-OHDA administration. During the period of 6-OHDA-induced lesion formation, the lipid families and species showed concentration fluctuations related to the recovery of behavior and nigrostriatal abnormalities. Correlation analysis showed that the levels of eicosanoids, CE, TG families, and TG (16:0_20:0_18:1) exhibited positive relationships with apomorphine-induced rotation behaviors and negative relationships with tyrosine hydroxylase (TH) expression in the midbrain. Conclusion: These results revealed that non-progressive nigrostriatal degeneration induced by 6-OHDA promotes the expression of an impairment-related lipidomic signature in CSF, and the level of eicosanoids, CE, TG families, and TG (16:0_20:0_18:1) in CSF may reveal pathological changes in the midbrain after 6-OHDA insult.

Bone-Derived Factors as Potential Biomarkers for Parkinson's Disease.

Background: Parkinson's disease (PD) and osteoporosis are both common aging diseases. It is reported that PD has a close relationship with osteoporosis and bone secretory proteins may be involved in disease progression. Objectives: To detect the bone-derived factors in plasma and cerebrospinal fluid (CSF) of patients with PD and evaluate their correlations with C-reaction protein (CRP) level, motor impairment, and Hoehn-Yahr (HY) stage of the disease. Methods: We included 250 PD patients and 250 controls. Levels of osteocalcin (OCN), osteopontin (OPN), osteoprotegerin (OPG), Sclerostin (SO), Bone morphogenetic protein 2 (BMP2), and Dickkopf-1 (DKK-1) in plasma and CSF were measured by custom protein antibody arrays. Data were analyzed using Mann-Whitney U-test and Spearman's receptor activator of NF-κB (RANK) correlation. Results: Plasma levels of OCN and OPN were correlated with CRP levels and HY stage and motor impairment of PD. Furthermore, the plasma assessment with CSF detection may enhance their potential prediction on PD. Conclusions: OCN and OPN may serve as potential biomarkers for PD. The inflammation response may be involved in the cross-talk between the two factors and PD.

A Novel Hydrogen Sulfide Donor Reduces Pilocarpine-Induced Status Epilepticus and Regulates Microglial Inflammatory Profile.

Although epilepsy is one of the most common neurologic disorders, there is still a lack of effective therapeutic drugs for it. Recently, we synthesized a novel hydrogen sulfide (H2S) donor, which is found to reduce seizures in animal models effectively. But it remains to be determined for its mechanism. In the present study, we found that the novel H2S donor could reduce pilocarpine-induced seizures in mice. It alleviated the epileptic behavior, the hippocampal electroencephalography (EEG) activity of seizures, and the damage of hippocampal neurons in status epilepticus mice. In addition, the novel H2S donor could reduce microglial inflammatory response. It not only reduced the upregulation of pro-inflammatory markers [inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2)] in status epilepticus mice, but also increased the levels of microglial anti-inflammatory marker arginase-1 (Arg-1). In lipopolysaccharide-treated microglia BV2 cells, administration of the H2S donor also significantly reduced the lipopolysaccharide-induced upregulation of the expression of the pro-inflammatory markers and increased the expression of the anti-inflammatory markers. Thus, the novel H2S donor regulates microglial inflammatory profile in status epilepticus mice and in vitro. These results suggested that the novel H2S donor can reduce seizures and regulate microglial inflammatory profile, which may be a novel mechanism and potential therapeutic strategy of the H2S donor anti-seizures.

Microglia provide structural resolution to injured dendrites after severe seizures.

Although an imbalance between neuronal excitation and inhibition underlies seizures, clinical approaches that target these mechanisms are insufficient in containing seizures in patients with epilepsy, raising the need for alternative approaches. Brain-resident microglia contribute to the development and stability of neuronal structure and functional networks that are perturbed during seizures. However, the extent of microglial contributions in response to seizures in vivo remain to be elucidated. Using two-photon in vivo imaging to visualize microglial dynamics, we show that severe seizures induce formation of microglial process pouches that target but rarely engulf beaded neuronal dendrites. Microglial process pouches are stable for hours, although they often shrink in size. We further find that microglial process pouches are associated with a better structural resolution of beaded dendrites. These findings provide evidence for the structural resolution of injured dendrites by microglia as a form of neuroprotection.