Degenerative Diseases Of Nervous System Research Articles

Auxiliary diagnosis of heterogeneous data of Parkinson’s disease based on improved convolution neural network

Parkinson’s disease (PD) is a kind of nervous system degenerative disease frequently occurring in the elderly over sixty years old. With the development of imaging technology, medical imaging has played a certain role in the diagnosis of Parkinson’s disease. The aim of the paper is to the diagnosis of Parkinson’s disease through deep learning. This paper selects the T2-MRI(T2-Magnetic Resonance Imaging) image and clinical data to diagnose Parkinson’s disease and integrates the heterogeneous data into the improved convolution neural network. In this paper, convolution neural network is added to the Gabor filter to make the whole convolution neural network have better effect; the activation function is improved and adjusted, which means the traditional sigmoid function and the tanh function are discarded, and the Relu activation function is used to improve the neural network. It is proved by experiments that the heterogeneous data diagnosis of T2-MRI image and clinical data (the accuracy is 77.9%) is better than the simple image data diagnosis (the accuracy is71.2%). For the same data, the improved convolution neural network is superior to the traditional network (the accuracy is 64.5%).

MicroRNA-203a-3p Regulates the Apoptosis of MPP+ Induced SH-SY5Y Cells by Targeting A-Synuclein

Parkinson's disease (PD) is a universal central nervous system degenerative diseases and has a serious impact on people's lives. MicroRNA-203a-3p (miR-203a-3p) is a tumor-inhibiting factor. Nevertheless, the role and mechanism of miR-203a-3p in PD remain unclear. Therefore, this investigated the role and underlying mechanism of miR-203a-3p in PD. Firstly, we have established a PD cell model by treating SH-SY5Y cells with MMP+. We found that cell viability gradually decreased with increased MMP+ concentration. Subsequently, we choose 2000 μM MMP+ for subsequent experiments. Then, qRT-PCR assay demonstrated that miR-203a-3p was down-regulated in MMP+ treated SH-SY5Y cells. Next, results from TargetScan and dual luciferase reporter gene assay suggested that a-synuclein (SNCA), an important genetic risk factor of PD, had direct binding sites with miR-203a-3p. Subsequently, we confirmed that miR-203a-3p negatively regulated SNCA expression in SH-SY5Y cells. Finally, we investigated the influence of miR-203a-3p on MMP+ -induced SH-SY5Y cells. CCK-8 assay results showed that MMP + reduced cell proliferation and induced apoptosis were inhibited by miR-203a-3p up-regulation. In addition, we found that MMP+ enhanced expression of SNCA, p53 and cleaved Caspase-3 proteins was reduced by miR-203a-3p overexpression. However, these changes were reversed by SNCA-plasmid. In conclusion, miR-203a-3p regulated the apoptosis of MPP+ induced SH-SY5Y cells by targeting SNCA. miR-203a-3p/SNCA axis might be a new latent targets for PD therapy.

Should mast cells be considered therapeutic targets in multiple sclerosis?

Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.

Comparative study of striatum GABA concentrations and magnetic resonance spectroscopic imaging in Parkinson's disease monkeys

BackgroundParkinson's disease is a progressive degenerative nervous system disease. Recent studies have shown that secondary changes in the GABA system play directly affect the pathogenesis of PD. There is still much debate about GABA concentrations because currently, GABA concentrations in the brain tissue are obtained indirectly by measuring its concentration in the blood and cerebrospinal fluid. These results are unreliable. Magnetic resonance spectroscopy (MRS) is the only noninvasive method for evaluating the concentration of metabolites in living brain tissue and has been widely applied in research and clinical practice. In addition, combining MEGA-PRESS technology with LCModel software for quantitative GABA measurements is largely recognized. At present, the PD monkeys model in primates has been increasingly proficient. Primates are more similar to humans in terms of brain structure and function than other animals. However, 3.0 T MRS studies involving the PD monkey model to measure metabolites in living subjects with PD are still rare. The study was performed at 3.0 T MRI with control monkeys and PD monkeys that were injected methyl-phenyl-tetrahydropyridine (MPTP) in one side of common carotid artery before and 3 months after successful model establishment to measure GABA concentrations in the bilateral striatum. Behavioral observations were performed for all animals, and the behavioral score was recorded. After 3 months, the GABA concentration in the bilateral striatum was measured in both groups by high-performance liquid chromatography (HPLC). The data obtained from magnetic resonance spectroscopy (MRS) were compared with the actual measured GABA concentrations in tissues isolated from the corresponding regions, and their correlations with the behavior score were analyzed. The research objectives are to investigate the changes of γ-aminobutyric acid (GABA) concentration in the bilateral striatum of monkeys with Parkinson's disease (PD) and the value of quantitatively measuring its concentration by noninvasive 3.0 T spectroscopy.Results(1) The MRS results showed that the GABA concentration in the injured side of the striatum of the PD monkeys was higher than in the contralateral side, but the difference was not statistically significant (P = 0.154). Compared with that the blank control group, the GABA concentration in the striatum of the PD monkeys increased, but there was no difference between the groups (P = 0.381; P = 0.425). (2) The GABA concentration that determined from the isolated specimens by HPLC in the injured side of the striatum of the PD monkeys was significantly higher than that in the contralateral side (P < 0.01). Compared with the blank control group, the PD monkeys had higher GABA concentrations in both sides of the striatum, and there was a significant difference in the lesion side (P = 0.004), while there was a non-significant difference in the contralateral side (P = 0.475). (3) The mean GABA concentration in the injured striatum of PD monkeys determined by MRS was not significantly correlated with the behavioral score (r = 0.146, P = 0.688). The mean GABA concentration in the injured striatum determined from the isolated specimens was positively correlated with the behavioral score in the same period (r = 0.444, P = 0.038).ConclusionThe GABA concentration in the injured striatum of PD monkeys is increased and positively correlated with behavioral changes. Validity of noninvasive 3.0 T MRS to detect PD neurotransmitter changes is limited.

Assessment of prevalence of cardiovascular risk factors among AMI patients

Background: Among the most common chronic diseases that afflict humans worldwide are diabetes, cardiovascular diseases (CVDs), osteoporosis, arthritis, obesity, chronic obstructive pulmonary disease, inflammatory bowel disease, central nervous system degenerative diseases and some cancers. Hence; the present study was undertaken for assessing the prevalence of cardiovascular risk factors among acute myocardial infarction (AMI) population. Materials & Methods: A total of 200 AMI subjects were enrolled in the present study. Complete demographic details of all the patients were obtained. A self-framed questionnaire was given to all the subjects for obtaining the complete medical, clinical and demographic of all the patients.Socio-economic status was defined on basis of modified Kuppuswamy’s Scale, according to which, Socio-economic classes were divided into upper, middle and lower. Blood samples were obtained from all the patients for assessing the hematological and biochemical profile. Results: Significant results were obtained while assessing the age-wise correlation of patients. There were 110 males and 90 females in the present study. 33.5 percent of the patients belonged to upper class, while 365 percent of the patients belonged to middle class. 30 percent of the patients belonged to lower class. Significantly higher number of diabetic and hypertensive patients was seen in the present study. Conclusion: Diabetes, hypertension and increasing age were found to be significant cardiovascular risk factors.

Naringenin Produces Neuroprotection Against LPS-Induced Dopamine Neurotoxicity via the Inhibition of Microglial NLRP3 Inflammasome Activation.

Background: Parkinson's disease (PD) is the second most prevalent central nervous system (CNS) degenerative disease and characterized by slow and progressive loss of dopamine (DA) neurons in the midbrain substantia nigra. Microglia-mediated neuroinflammation has been considered as the major central event in the process of DA neuronal loss. Thus, inhibition of neuroinflammation could possess a more viable strategy for PD treatment. Naringenin (NAR), a natural flavanoid contained in citrus fruit and grapefruits, possesses amounts of pharmacological activities. Recent studies indicated that NAR produced neuroprotection against several neurological disorders. However, the mechanisms underlying NAR-generated neuroprotection are not fully illuminated.Methods: In the present study, rat nigral stereotaxic injection of lipopolysaccharide (LPS)-induced DA neuronal loss was performed to investigate NAR-mediated neuroprotection. In addition, BV-2 and MN9D cell lines were applied to explore the underlying mechanisms.Results: NAR protected DA neurons against LPS-induced neurotoxicity. Also, NAR suppressed microglial nod-like receptor protein 3 (NLRP3) inflammasome signaling activation and the subsequent pro-inflammatory factors release. In addition, NAR-mediated DA neuroprotection was dependent on the inhibition of microglial NLRP3 inflammasome activation, as evidenced by the observations that NAR-reduced pro-inflammatory factors production and further NAR-exerted DA neuroprotection against LPS-induced neuronal damage was not discerned after microglial NLRP3 siRNA treatment.Conclusions: This study demonstrated that NAR targeted microglial NLRP3 inflammasome to protect DA neurons against LPS-induced neurotoxicity. These findings suggest NAR might hold a promising therapeutic potential for PD.

Moderating effects of crocin on some stress oxidative markers in rat brain following demyelination with ethidium bromide

BackgroundThe purpose of this study was to investigate the effects of Crocin on oxidative markers (GPx, SOD, MDA) in animal model of demyelination with Ethidium bromide (EB). MethodsFemale Wistar rats were assigned in to 4 groups; Sham, with no receiving any agent (Sham), Sham Operated group with injection of EB into the brain received no agent (SO), Sham Treatment group with injection of EB and receiving PBS as vehicle and Treatment group with injection of EB and receiving Crocin (100 mg/kg). Demyelination was induced by single dose injection of 10 μl of EB 0.1% into the Cisterna magna of the brain. Crocin was diluted and applied to each animal for 21 days, once per day gavage. The levels of oxidative markers (GPx, SOD and MDA) were measured by related standard kits. Data were analyzed by paired t-test and ANOVA with post hoc test. ResultsThe results showed that crocin decreases the levels of GPx and SOD significantly as well as MDA level after 21 days (α ≤ 0.05). In addition, results showed that there were significant differences in the GPx, SOD and MDA levels between all groups at post treatment phase (α ≤ 0.05). ConclusionIt can be concluded that crocin can moderate the level of oxidative markers after demyelination of the brain cells in MS cases. Due to this effect, crocin can be considered as an effective anti-oxidant in management of degenerative nervous system diseases.

Research progress on the intervening effects of active components of Chinese herbs on amyloid-beta-induced injury of neural cells

Alzheimer's disease is a common clinical central nervous system degenerative disease. From 1906, it has not yet been clearly revealed the pathogenesis, and there are no clinically safe and effective drugs. Amyloid-beta (Aβ) cascade reaction theory is currently recognized as the pathogenesis. Aβ deposition of neurotoxicity is an important part of the pathogenesis. There are Aβ-induced inflammation of the central nervous and oxidative stress-induced apoptosis induced by a variety of ways leading to neuronal dysfunction and death. This article summarizes the active ingredients of traditional Chinese medicine that has a protective effect on Aβ toxicity in recent years. Traditional Chinese medicine mainly through the antiapoptosis, antioxidation, and anti-inflammatory reduces Aβ production and deposition of Aβ on the protection of nerve cell injury.

Proteomic Study of a Parkinson's Disease Model of Undifferentiated SH-SY5Y Cells Induced by a Proteasome Inhibitor.

Parkinson's disease (PD) is one of the most common nervous system degenerative diseases. However, the etiology of this disease remains elusive. Here, a proteasome inhibitor (PSI)-induced undifferentiated SH-SY5Y PD model was established to analyze protein alterations through proteomic study. Methods: Cultured undifferentiated SH-SY5Y cells were divided into a control group and a group treated with 2.5 µM PSI (PSI-treated group). An methyl thiazolyl tetrazolium (MTT) assay was applied to detect cell viability. Acridine orange/ethidium bromide (AO/EB), α-synuclein immunofluorescence and hematoxylin and eosin (H&E) staining were applied to evaluate apoptosis and cytoplasmic inclusions, respectively. The protein spots that were significantly changed were separated, analyzed by 2D gel electrophoresis and DIGE De Cyder software, and subsequently identified by MALDI-TOF mass spectrometry and database searching. Results: The results of the MTT assay showed that there was a time and dose dependent change in cell viability following incubation with PSI. After 24 h incubation, PSI resulted in early apoptosis, and cytoplasmic inclusions were found in the PSI-treated group through H&E staining and α-synuclein immunofluorescence. Thus, undifferentiated SH-SY5Y cells could be used as PD model following PSI-induced inhibition of proteasomal function. In total, 18 proteins were differentially expressed between the groups, 7 of which were up-regulated and 11 of which were down-regulated. Among them, 5 protein spots were identified as being involved in the ubiquitin proteasome pathway-induced PD process. Conclusions: Mitochondrial heat shock protein 75 (MTHSP75), phosphoglycerate dehydrogenase (PHGDH), laminin binding protein (LBP), tyrosine 3/tryptophan 5-monooxygenase activation protein (14-3-3ε) and YWHAZ protein (14-3-3ζ) are involved in mitochondrial dysfunction, serine synthesis, amyloid clearance, apoptosis process and neuroprotection. These findings may provide new clues to deepen our understanding of PD pathogenesis.

Retinal screening for dementia

Dr Douglas Clarkson looks at how developments in medical screening techniques are showing promise in the identification and monitoring of central nervous system degenerative diseases such as Alzheimer's disease.

Chapter 29 - Spinal cord

We first present a brief historic review of developments in the understanding of spinal cord clinical neuroanatomy and neurophysiology over the past 200 years. We then discuss the technical aspects that apply to the examination of the human spinal cord giving details on the interrelations between the spinal cord and the overlying structures, including the meninges and vertebrae. The subsequent discussion focuses on diseases of the spinal cord. Diseases that affect the spinal cord are vascular disease, diseases of spinal column, trauma, developmental abnormalities, central nervous system degenerative disease, inflammatory disease, metabolic and nutritional myelopathies, and tumors. We summarize our knowledge regarding general reactions of spinal cord tissue to disease, in particular Wallerian degeneration of descending/ascending tracts and axonal reaction. Two categories of disease will be covered in depth: vascular disease of the spinal cord, including a review of normal vascular anatomy, and diseases of the vertebral column that can affect the cord secondarily.

Mortality for chronic-degenerative diseases in Tuscany: Ecological study comparing neighboring areas with substantial differences in environmental pollution.

Environmental pollution is associated with morbidity and mortality for chronic-degenerative diseases. Recent data points out a relationship between proximity to industrial plants and mortality due to neoplasms. The aim of this study has been to compare mortality due to chronic-degenerative diseases in the area of Tuscany (Bassa Val di Cecina), Italy, characterized by the presence of 2 neighboring municipalities similar in terms of size but with substantial differences in industrial activities: Rosignano (the site of chemical, energy production and waste processing industries) and Cecina (with no polluting activity). Standardized mortality rates for the 2001-2010 decade were calculated; the data of the whole Tuscany was assumed as reference. Environmental levels of pollutants were obtained by databases of the Environmental Protection Agency of Tuscany Region (Agenzia Regionale per la Protezione Ambientale della Toscana - ARPAT). Maximum tolerated pollutant levels set by national laws were assumed as reference. In the whole Bassa Val di Cecina, significantly elevated standardized mortality rates due to mesothelioma, ischemic heart diseases, cerebrovascular diseases and Alzheimer and other degenerative diseases of nervous system were observed. In the municipality of Rosignano, a significant excess of mortality for all these groups of diseases was confirmed. On the contrary, the municipality of Cecina showed only significantly higher mortality rates for ischemic heart diseases. Elevated levels of heavy metals in sea water and of particulate matter which contains particles of diameter ≤ 10 mm (PM10) and ozone in air were detected in Rosignano. This study shows an excess of mortality for chronic-degenerative diseases in the area with elevated concentration of polluting factories. Proximity to industrial plants seems to represent a risk factor for those diseases. Int J Occup Med Environ Health 2017;30(4):641-653.

Hydrolysis and Dissolution of Amyloids by Catabodies.

Catalytic antibodies (catabodies) hold potential for superior immunotherapy because of their turnover capability and no or minimal induction of inflammatory responses. Catabodies neutralize and remove target antigens more potently than conventional antibodies. Depending on the catalytic rate constant, a single catabody molecule degrades thousands to millions of target molecules over its useful lifespan, whereas conventional antibodies only form reversibly associated, stoichiometric complexes with the target. Thus, removal of the antibody-bound target requires accessory phagocytic cells that ingest the immune complexes, which is usually accompanied by release of inflammatory mediators. In comparison, catabodies bind the target only transiently, and the rapid and direct target destruction reduces the concentration of immune complexes that can activate inflammatory processes. These features are especially pertinent when large target amounts at anatomically vulnerable sites must be removed, e.g., amyloids. We reported specific catabodies to misfolded transthyretin (misTTR) amyloid and amyloid β peptide (Aβ). Accumulation of the oligomeric and fibrillized amyloid TTR forms causes diverse systemic pathologies, including cardiomyopathy, polyneuropathy, and skeletal diseases. Brain Aβ aggregates are thought to cause central nervous system degenerative disease, chiefly Alzheimer's disease. We describe methods for testing catabody-mediated degradation and dissolution of Aβ and TTR.

DEMENTIA MORTALITY IN THE UNITED STATES: 2000–2014

Objectives-This report presents data on mortality attributable to dementia. Data for dementia as an underlying cause of death from 2000 through 2017 are shown by selected characteristics such as age, sex, race and Hispanic origin, and state of residence. Trends in dementia deaths overall and by specific cause are presented. The reporting of dementia as a contributing cause of death is also described. Methods-Data in this report are based on information from all death certificates filed in the 50 states and the District of Columbia. Using multiple cause-of-death data files, dementia is considered to include deaths attributed to unspecified dementia; Alzheimer disease; vascular dementia; and other degenerative diseases of nervous system, not elsewhere classified. Results-In 2017, a total of 261,914 deaths attributable to dementia as an underlying cause of death were reported in the United States. Forty-six percent of these deaths were due to Alzheimer disease. In 2017, the age-adjusted death rate for dementia as an underlying cause of death was 66.7 deaths per 100,000 U.S. standard population. Age-adjusted death rates were higher for females (72.7) than for males (56.4). Death rates increased with age from 56.9 deaths per 100,000 among people aged 65-74 to 2,707.3 deaths per 100,000 among people aged 85 and over. Age-adjusted death rates were higher among the non-Hispanic white population (70.8) compared with the non-Hispanic black population (65.0) and the Hispanic population (46.0). Age-adjusted death rates for dementia varied by state and urbanization category. Overall, age-adjusted death rates for dementia increased from 2000 to 2017. Rates were steady from 2013 through 2016, and increased from 2016 to 2017. Patterns of reporting the individual dementia causes varied across states and across time.

ESE1 is Associated with Neuronal Apoptosis in Lipopolysaccharide Induced Neuroinflammation.

Neuronal apoptosis induced by the over-activation of microglia during neuroinflammation contributes to the pathology of central nervous system (CNS) degenerative diseases. ESE1 regulates apoptosis of intestinal epithelial cells in ulcerative colitis via accelerating NF-κB activation. NF-κB activation participates in neuronal apoptosis. However, the expression and functions of ESE1 in neuronal apoptosis during CNS inflammatory response remain unclear. In present study, ESE1 expression significantly increased in cerebral cortex after lipopolysaccharide (LPS) intracerebroventricular injection. Immunofluorescence staining indicated that ESE1 was located in neurons. Furthermore, there was a concomitant up-regulation of apoptotic markers including active caspase-3, BAX and decreased expression of anti-apoptosis protein Bcl-2. In vitro, ESE1 depletion in cortical primary neurons inhibited active caspase-3 and BAX expression as well as lactate dehydrogenase (LDH) release with up-regulation of Bcl-2, while ESE1 overexpression can exert opposite effects, indicating that ESE1 promoted neuronal apoptosis induced by LPS or LPS exposed microglia conditioned media (CM). ESE1 accelerated NF-κB activation in neurons with CM treatment. Collectively, all these data suggested that ESE1 might boost neuronal apoptosis during neuroinflammation via up-regulating NF-κB activation. These findings have implications on the potential target of ESE1 in CNS inflammation treatment.

An In Vivo Pharmacological Screen Identifies Cholinergic Signaling as a Therapeutic Target in Glial-Based Nervous System Disease.

Despite the urgent need for better treatments for neurological diseases, drug development for these devastating disorders has been challenging. The effectiveness of traditional large-scale in vitro screens may be limited by the lack of the appropriate molecular, cellular, and structural environment. Using a simple Drosophila model of Alexander disease, we performed a moderate throughput chemical screen of FDA-approved drugs and natural compounds, and found that reducing muscarinic cholinergic signaling ameliorated clinical symptoms and oxidative stress in Alexander disease model flies and mice. Our work demonstrates that small animal models are valuable screening tools for therapeutic compound identification in complex human diseases and that existing drugs can be a valuable resource for drug discovery given their known pharmacological and safety profiles.

A fibrin matrix promotes the differentiation of EMSCs isolated from nasal respiratory mucosa to myelinating phenotypical Schwann-like cells.

Because Schwann cells perform the triple tasks of myelination, axon guidance and neurotrophin synthesis, they are candidates for cell transplantation that might cure some types of nervous-system degenerative diseases or injuries. However, Schwann cells are difficult to obtain. As another option, ectomesenchymal stem cells (EMSCs) can be easily harvested from the nasal respiratory mucosa. Whether fibrin, an important transplantation vehicle, can improve the differentiation of EMSCs into Schwann-like cells (SLCs) deserves further research. EMSCs were isolated from rat nasal respiratory mucosa and were purified using anti-CD133 magnetic cell sorting. The purified cells strongly expressed HNK-1, nestin, p75NTR, S-100, and vimentin. Using nuclear staining, the MTT assay and Western blotting analysis of the expression of cell-cycle markers, the proliferation rate of EMSCs on a fibrin matrix was found to be significantly higher than that of cells grown on a plastic surface but insignificantly lower than that of cells grown on fibronectin. Additionally, the EMSCs grown on the fibrin matrix expressed myelination-related molecules, including myelin basic protein (MBP), 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNPase) and galactocerebrosides (GalCer), more strongly than did those grown on fibronectin or a plastic surface. Furthermore, the EMSCs grown on the fibrin matrix synthesized more neurotrophins compared with those grown on fibronectin or a plastic surface. The expression level of integrin in EMSCs grown on fibrin was similar to that of cells grown on fibronectin but was higher than that of cells grown on a plastic surface. These results demonstrated that fibrin not only promoted EMSC proliferation but also the differentiation of EMSCs into the SLCs. Our findings suggested that fibrin has great promise as a cell transplantation vehicle for the treatment of some types of nervous system diseases or injuries.

A large, nationwide, longitudinal study of central nervous system diseases among Korean workers exposed to manganese.

In occupational epidemiologic studies, the low incidence and chronic process of central nervous system (CNS) diseases has complicated the determination of the relationship between increased morbidity and manganese (Mn) exposure. Therefore, through this large cohort study, we evaluated CNS disease morbidity among Korean workers exposed to Mn Data were collected from Mn-associated specialized medical check-up 2000 and 2004 in Korea. The number of workers admitted to hospital because of clinically diagnosed CNS disease was analyzed in male workers exposed to Mn (n = 104,544). As a control reference population, 2% of Korean men were randomly selected and their hospital admission data were analyzed. For Mn-exposed workers, Standardized admission ratios (SARs) for CNS disease, as determined by ICD-10 classifications, were estimated in reference to the control population During follow up, 64 workers admitted because of CNS diseases. Chronic exposure to Mn (≥ 10 years) was significantly associated with the SAR (95% CI) of extrapyramidal and movement disorders (SAR: 2.03, 95% CI: 1.05-3.55), in particular, other extrapyramidal and movement disorders (SAR: 4.81, 95% CI: 1.29-12.32). Also borderline association (SAR = 4.88, 90% CI: 1.05-7.04) was noted for secondary Parkinsonism among workers with chronic Mn exposure. SARs (95% CI) for other degenerative nervous system diseases were significantly higher in Mn-exposed workers compared with the control population (SAR: 3.60, 95% CI: 1.16-8.40) CONCLUSION: In conclusion, Mn-exposed workers exhibited significantly elevated SARs for degenerative nervous system diseases and extrapyramidal and movement disorders, compared to the age-matched reference population, suggesting a relatedness with Mn exposure.

Prof. Dongsheng Fan: turn off the amyotrophic lateral sclerosis's disease gene.

With more and more celebrities all over the world jumping on the bandwagon of the Ice Bucket Challenge, amyotrophic lateral sclerosis (ALS) has been put in the spotlight. Though this event in a way had risen the awareness of ALS, there are still so many unsolved problems about it, such as the difficulty of accurate diagnosis and complete treatment. To discuss the hotspots and recent advances in this area, Annals of Translational Medicine has the pleasure to invite Prof. Dongsheng Fan (Figure 1), one of the leading experts on degenerative diseases of the nervous system in China, to unveil the “mystery” of ALS and find out what’s newest about this disease. Prof. Fan will also work on a special issue about ALS as the guest editor of Annals of Translational Medicine subsequently.

Exploration of the Pathogenesis of Amyotrophic Lateral Sclerosis from the Perspective of Motor Neuron TDP-43 Protein Expression and ADAR2 Activity

Amyotrophic lateral sclerosis (ALS) is a common adult-onset nervous system degenerative disease, characterized by the progressive loss of upper and lower motor neurons. TDP-43 pathology in motor neurons is a hallmark of ALS. In addition, the reduced expression of an RNA-editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2), increases the expression of GluA2 at an unedited glutamine/arginine (Q/R) site in the motor neurons of patients with sporadic ALS. The change in the amino acid residue at the Q/R site of GluR2 results in marked alterations in channel properties of AMPA receptors, which increases Ca²⁺ permeability, and this increase in Ca²⁺ influx plays a key role in the death of motor neurons. ADAR2 mRNA is a target RNA for TDP-43, and TDP-43 plays a regulatory role in the expression of ADAR2. Recently, researchers have explored the possibility of gene therapy for ALS by upregulating ADAR2 in mouse motor neurons using an adeno-associated virus serotype 9 (AAV9) vector that enables gene delivery to a wide array of central neurons after peripheral administration and observed that the expression of exogenous ADAR2 in the central neurons effectively prevented progressive motor dysfunction. AAV9-ADAR2 rescued the motor neurons from death by normalizing TDP-43 expression. Therefore, this AAV9-mediated ADAR2 gene delivery may enable the development of a gene therapy for ALS. i 2014 S. Karger AG, Basel