Multifaceted superoxide dismutase 1 expression in amyotrophic lateral sclerosis patients:a rare occurrence?

Amyotrophic lateral sclerosis(ALS)is a neuromuscular condition resulting from the progressive degeneration of motor neurons in the cortex,brainstem,and spinal cord.While the typical clinical phenotype of ALS involves both upper and lower motor neurons,human and animal studies over the years have highlighted the potential spread to other motor and non-motor regions,expanding the phenotype of ALS.Although superoxide dismutase 1(SOD1)mutations represent a minority of ALS cases,the SOD1 gene remains a milestone in ALS research as it represents the first genetic target for personalized therapies.Despite numerous single case reports or case series exhibiting extramotor symptoms in patients with ALS mutations in SOD1(SOD1-ALS),no studies have comprehensively explored the full spectrum of extramotor neurological manifestations in this subpopulation.In this narrative review,we analyze and discuss the available literature on extrapyramidal and non-motor features during SOD1-ALS.The multifaceted expression of SOD1 could deepen our understanding of the pathogenic mechanisms,pointing towards a multidisciplinary approach for affected patients in light of new therapeutic strategies for SOD1-ALS.

Monoamine alterations and rotational asymmetry in a rat model of Parkinson's disease following lateral ventricle transplantation of human amniotic epithelial cells

BACKGROUND： Human amniotic epithelial cells （HAECs） can differentiate into neurons, astrocytes and oligodendrocytes. They biologically secrete many active neurotrophins and have the capacity to metabolize dopamine enzymes. These features underlie a theoretical basis for the treatment of Parkinson＇s disease （PD）. OBJECTIVE： To investigate the survival and differentiation of transplanted HAECs in the lateral ventricle of PD model rats, and to explore its effect on circling behavior, as well as levels of dopamine （DA）, the metabolite homovanillic acid, dihydroxyphenyl acetic acid, 5-hydroxyindoleacetic acid, and 5-hydroxytryptamine in the striatum. DESIGN, TIME AND SETTING： A randomized, controlled, animal study was performed at the Institute of Biochemistry and Cell Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, and Shanghai Celstar Institute of Biotechnology from May 2007 to December 2008. MATERIALS： HAECs were derived from the placental chorion following caesarean delivery at the Shanghai International Matemal and Child Health Hospital. 6-hydroxydopamine （6-OHDA）, and mouse anti-human Vimentin monoclonal antibody were purchased from Sigma, USA; mouse anti-human nestin and tyrosine hydroxylase （TH） monoclonal antibodies were purchased from Chemicon, USA. METHODS： A total of 114 healthy, adult, Sprague Dawley rats were randomly assigned to two groups： PD model [n = 90, stereotactic microinjection of 2 μL 6-OHDA （3.5 μg/uL） into the striatum] and control （n = 24, no treatment）. The 51 successful PD model rats were randomly divided into 3 subgroups （n = 17）： HAEC, PBS, and model. The HAEC and PBS groups were respectively injected with 10 μL PBS solution containing 1 × 10^5/mL HAECs or 10 pL PBS into the lateral ventricle. The model group was not treated. MAIN OUTCOME MEASURES： TH protein expression in the striatum was evaluated by immunohistochemistry 5 weeks after HAEC transplantation. At 10 weeks, HAEC survival in the lateral ventricle was investigated by immunofluorescent staining; differentiation of HAECs in the lateral and third ventricles was examined by TH immunohistochemistry; concentrations of DA, homovanillic acid, dihydroxyphenyl acetic acid, 5-hydroxyindoleacetic acid, and 5-hydroxytryptamine in the striatum, as well as DA concentration in the cerebrospinal fluid, were measured with high-performance liquid chromatography-electrochemical detection. Circling behavior of PD model rats was consecutively observed for 10 weeks following intraperitoneal injection of amphetamine 1 week after successful model establishment. RESULTS： tn the HAEC group, the number of TH-positive cells significantly increased in the striatum, and circling behavior significantly decreased, compared with the PBS and model groups （P 〈 0.01）. In addition, monoamine concentrations in the striatum, as well as DA concentrations in the cerebrospinal fluid, significantly increased, compared with the PBS group （P 〈 0.05-0.01）. Moreover, a large number of nestin-, vimentin-, and TH-positive cells were observed in the lateral and third ventricles following HAEC injection.CONCLUSION： HAECs survived for 10 weeks with no overgrowth following transplantation into the lateral ventricle of PD model rats. Moreover, the cells differentiated into dopaminergic neurons, which increased DA secretion. HAEC transplantation improved cycling behavior in PD model rats.

Pretreatment of caffeine leads to partial neuroprotection in MPTP model of Parkinson＇s disease

Parkinson＇s disease （PD） is disorder affecting more than a common neurodegenerative 1% people above 60 years of age worldwide, manifesting as the impaired motor function such as tremors, rigidity, akinesia/bradykinesia and postural inefficiency with a reduced life expectancy （Dorsey et al., 2007）. PD is believed to be the end result of the progressive death of dopaminergic neurons in the substantia nigra pars compacta （SNc）.

The role of exosomes in adult neurogenesis:implications for neurodegenerative diseases

Exosomes are cup-shaped extracellular vesicles with a lipid bilayer that is approximately 30 to 200 nm in thickness.Exosomes are widely distributed in a range of body fluids,including urine,blood,milk,and saliva.Exosomes exert biological function by transporting factors between different cells and by regulating biological pathways in recipient cells.As an important form of intercellular communication,exosomes are increasingly being investigated due to their ability to transfer bioactive molecules such as lipids,proteins,mRNAs,and microRNAs between cells,and because they can regulate physiological and pathological processes in the central nervous system.Adult neurogenesis is a multistage process by which new neurons are generated and migrate to be integrated into existing neuronal circuits.In the adult brain,neurogenesis is mainly localized in two specialized niches:the subventricular zone adjacent to the lateral ventricles and the subgranular zone of the dentate gyrus.An increasing body of evidence indicates that adult neurogenesis is tightly controlled by environmental conditions with the niches.In recent studies,exosomes released from different sources of cells were shown to play an active role in regulating neurogenesis both in vitro and in vivo,thereby participating in the progression of neurodegenerative disorders in patients and in various disease models.Here,we provide a state-of-the-art synopsis of existing research that aimed to identify the diverse components of exosome cargoes and elucidate the therapeutic potential of exosomal contents in the regulation of neurogenesis in several neurodegenerative diseases.We emphasize that exosomal cargoes could serve as a potential biomarker to monitor functional neurogenesis in adults.In addition,exosomes can also be considered as a novel therapeutic approach to treat various neurodegenerative disorders by improving endogenous neurogenesis to mitigate neuronal loss in the central nervous system.

Mitophagy in neurodegenerative disease pathogenesis

Mitochondria are critical cellular energy resources and are central to the life of the neuron.Mitophagy selectively clears damaged or dysfunctional mitochondria through autophagic machinery to maintain mitochondrial quality control and homeostasis.Mature neurons are postmitotic and consume substantial energy,thus require highly efficient mitophagy pathways to turn over damaged or dysfunctional mitochondria.Recent evidence indicates that mitophagy is pivotal to the pathogenesis of neurological diseases.However,more work is needed to study mitophagy pathway components as potential therapeutic targets.In this review,we briefly discuss the characteristics of nonselective autophagy and selective autophagy,including ERphagy,aggrephagy,and mitophagy.We then introduce the mechanisms of Parkin-dependent and Parkin-independent mitophagy pathways under physiological conditions.Next,we summarize the diverse repertoire of mitochondrial membrane receptors and phospholipids that mediate mitophagy.Importantly,we review the critical role of mitophagy in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.Last,we discuss recent studies considering mitophagy as a potential therapeutic target for treating neurodegenerative diseases.Together,our review may provide novel views to better understand the roles of mitophagy in neurodegenerative disease pathogenesis.

Antisense therapy:a potential breakthrough in the treatment of neurodegenerative diseases

Neurodegenerative diseases are a group of disorders characterized by the progressive degeneration of neurons in the central or peripheral nervous system.Currently,there is no cure for neurodegenerative diseases and this means a heavy burden for patients and the health system worldwide.Therefore,it is necessary to find new therapeutic approaches,and antisense therapies offer this possibility,having the great advantage of not modifying cellular genome and potentially being safer.Many preclinical and clinical studies aim to test the safety and effectiveness of antisense therapies in the treatment of neurodegenerative diseases.The objective of this review is to summarize the recent advances in the development of these new technologies to treat the most common neurodegenerative diseases,with a focus on those antisense therapies that have already received the approval of the U.S.Food and Drug Administration.

Intracerebroventricular transplanted bone marrow stem cells survive and migrate into the brain of rats with Parkinson's disease

In this study, 6-hydroxydopamine was stereotaxically injected into the right substantia nigra compact and ventral tegmental area of rats to establish Parkinson＇s disease models. The rats then received a transplantation of bone marrow stromal cells that were previously isolated, cultured and labeled with 5-bromo-2＇-deoxyuridine in vitro. Transplantation of the bone marrow stromal cells significantly decreased apomorphine-induced rotation time and the escape latency in the Morris water maze test as compared with rats with untreated Parkinson＇s disease. Immunohistochemical staining showed that, 5-bromo-2＇-deoxyuridine-immunoreactive cells were present in the lateral ventricular wall and the choroid plexus 1 day after transplantation. These immunoreactive cells migrated to the surrounding areas of the lateral cerebral ventricle along the corpus callosum. The results indicated that bone marrow stromal cells could migrate to tissues surround the cerebral ventricle via the cerebrospinal fluid circulation and fuse with cells in the brain, thus altering the phenotype of cells or forming neuron-like cells or astrocytes capable of expressing neuron-specific proteins. Taken together, the present findings indicate that bone marrow stromal cells transplanted intracerebroventricularly could survive, migrate and significantly improve the rotational behavior and cognitive function of rats with experimentally induced Parkinson＇s disease.

Deep brain stimulation of the subthalamic nucleus treats Parkinson's disease through enhancing metabolic activity of the corpus striatum Verification by single photon emission computed tomography and positron emission tomography

BACKGROUND： Subthalamic nucleus deep brain stimulation （STN DBS） for Parkinson＇s disease （PD） has achieved good effects, but to date the mechanism of STN DBS remains poorly understood STN DBS may increase dopamine levels or metabolic activity of the corpus striatum. OBJECTIVE： To validate the effects of STN DBS on dopamine metabolism and glucose metabolism in the corpus striatum of hemiparkinsonian monkeys using single photon emission computed tomography （SPECT） and position emission tomography （PET）. DESIGN, TIME AND SET＇rING： A controlled animal study was performed at the Neurosurgery Laboratory, Changhai Hospital of the Second Military Medical University of Chinese PLA between January 2004 and December 2007. METHODS： Hemiparkinsonism was induced in adult Rhesus Macaque monkeys, which exhibit similar characteristics of PD in humans, through unilateral internal carotid artery infusion of 1-methy-4-phenyl-1, 2, 3, 6-tetrahydropyrindine. Following model establishment, stimulation electrodes were implanted in the right STN, and chronic high-frequency stimulation （60 μs pulse width, 130 Hz frequency, and 1.5-2.0 V pressure） was performed. MAIN OUTCOME MEASURES： The changes in dopamine transporter （DAT）, D2 receptor （D2R）, and glucose metabolism in the corpus striatum following STN DBS were observed using SPECT and PET. RESULTS： SPECT examination showed that DAT specific binding in the right corpus striatum was increased at 3 months after DBS compared with prior to stimulation, and D2R specific binding in the right corpus striatum gradually decreased near levels on the left （non-electrode-implanted） side within 3 months after DBS. PET examination showed that the glucose metabolism in the right corpus striatum was markedly increased at 3 months after effective DBS. Hemiparkinsonism monkeys showed improved left limb rigidity, increased activities, and stable gait under chronic high-frequency stimulation. CONCLUSION： STN DBS increased striatal DAT, decreased D2R, and enhanced glucose metabolism, suggesting that chronic, high-frequency STN stimulation enhanced the metabolic activity of the corpus striatum, a mechanism for improving the PD symptoms of hemiparkinsonian monkeys.

The interaction between the dopaminergic and the serotonergic systems in the 6-OHDA rat model of Parkinson’s disease

This review summarizes published results that are related to the coupling between the dopaminergic and the serotonergic systems and their association to Parkinson’s disease. We focus on the 6-hydroxydopamine rat model of Parkinson’s disease to better understand how dopamine dysfunction affects the serotonergic system, and furthermore to investigate whether a bidi-rectional coupling exists and how it affects functionality and behavior. The accumulated evidence supports a proposed mechanism for this coupling that evolves the lateral habenula.

Mitophagy links oxidative stress conditions and neurodegenerative diseases

Mitophagy is activated by a number of stimuli, including hypoxia, energy stress, and increased oxidative phosphorylation activity. Mitophagy is associated with oxidative stress conditions and central neurodegenerative diseases. Proper regulation of mitophagy is crucial for maintaining homeostasis; conversely, inadequate removal of mitochondria through mitophagy leads to the generation of oxidative species, including reactive oxygen species and reactive nitrogen species, resulting in various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. These diseases are most prevalent in older adults whose bodies fail to maintain proper mitophagic functions to combat oxidative species. As mitophagy is essential for normal body function, by targeting mitophagic pathways we can improve these disease conditions. The search for effective remedies to treat these disease conditions is an ongoing process, which is why more studies are needed. Additionally, more relevant studies could help establish therapeutic conditions, which are currently in high demand. In this review, we discuss how mitophagy plays a significant role in homeostasis and how its dysregulation causes neurodegeneration. We also discuss how combating oxidative species and targeting mitophagy can help treat these neurodegenerative diseases.

Oxidative stress, mitochondrial damage and neurodegenerative diseases

Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2＋ homeostasis and mitochondrial defense systems. All these changes are implicated in the development of these neurodegenerative diseases, mediating or amplifying neuronal dysfunction and triggering neurodegeneration. This paper summarizes the contribution of oxidative stress and mitochondrial damage to the onset of neurodegenerative diseases and discusses strategies to modify mitochondrial dysfunction that may be attractive therapeutic interventions for the treatment of various neurodegenerative diseases.

Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases

Common neurodegenerative diseases of the central nervous system are characterized by progressive damage to the function of neurons, even leading to the permanent loss of function. Gene therapy via gene replacement or gene correction provides the potential for transformative therapies to delay or possibly stop further progression of the neurodegenerative disease in affected patients. Adeno-associated virus has been the vector of choice in recent clinical trials of therapies for neurodegenerative diseases due to its safety and efficiency in mediating gene transfer to the central nervous system. This review aims to discuss and summarize the progress and clinical applications of adeno-associated virus in neurodegenerative disease in central nervous system. Results from some clinical trials and successful cases of central neurodegenerative diseases deserve further study and exploration.

Long-noncoding RNAs as epigenetic regulators in neurodegenerative diseases

The growing and rapid development of high-throughput sequencing technologies have allowed a greater understanding of the mechanisms underlying gene expression regulation.Editing the epigenome and epitranscriptome directs the fate of the transcript influencing the functional outcome of each mRNA.In this context,non-coding RNAs play a decisive role in addressing the expression regulation at the gene and chromosomal levels.Long-noncoding RNAs,consisting of more than 200 nucleotides,have been shown to act as epigenetic regulators in several key molecular processes involving neurodegenerative disorders,such as Alzheimer’s disease,Parkinson’s disease,amyotrophic lateral sclerosis and Huntington’s disease.Long-noncoding RNAs are abundantly expressed in the central nervous system,suggesting that their deregulation could trigger neuronal degeneration through RNA modifications.The evaluation of their diagnostic significance and therapeutic potential could lead to new treatments for these diseases for which there is no cure.

Stem cell therapy in neurodegenerative diseases From principles to practice

The lack of curative therapies for neurodegenerative diseases has high economic impact and places huge burden on the society.The contribution of stem cells to cure neurodegenerative diseases has been unraveled and explored extensively over the past few years.Beyond substitution of the lost neurons,stem cells act as immunomodulators and neuroprotectors.A large number of preclinical and a small number of clinical studies have shown beneficial outcomes in this context.In this review,we have summarized the current concepts of stem cell therapy in neurodegenerative diseases and the recent advances in this field,particularly between 2010 and 2012.Further studies should be encouraged to resolve the clinical issues and vague translational findings for maximum optimization of the efficacy of stem cell therapy in neurodegenerative diseases.

Autophagy and its neuroprotection in neurodegenerative diseases

It has been suggested that protein misfolding and aggregation contribute significantly to the development of neurodegenerative diseases. Misfolded and aggregated proteins are cleared by ubiquitin proteasomal system （UPS） and by both Micro and Macro autophagy lysosomal pathway （ALP）. Autophagosomal dysfunction has been implicated in an increasing number of diseases including neurodegenerative diseases. Autophagy is a cellular self-eating process that plays an important role in neuroprotection as well as neuronal injury and death. While a decrease in autophagic activity interferes with protein degradation and possibly organelle turnover, increased autophagy has been shown to facilitate the clearance of aggregation-prone proteins and promote neuronal survival in a number of disease models. On the other hand, too much autophagic activity can be detrimental, suggesting the regulation of autophagy is critical in dictating cell fate. In this review paper, we will discuss various aspects of ALP biology and its dual functions in neuronal cell death and survival. We will also evaluate the role of autophagy in neurodegenerative diseases including Alzheimer＇s disease, Parkinson＇s disease, Huntington＇s disease, amyotrophic lateral sclerosis. Finally, we will explore the therapeutic potential of autophagy modifiers in several neurodegenerative diseases.

Targeting prion-like protein spreading in neurodegenerative diseases

The infectious template-mediated protein conversion is a unique mechanism for the onset of rare and fatal neurodegenerative disorders known as transmissible spongiform encephalopathies, or prion diseases, which affect humans and other animal species. However, emerging studies are now demonstrating prion-like mechanisms of self-propagation of protein misfolding in a number of common, non-infectious neurodegenerative diseases such as Alzheimer＇s disease and Parkinson＇s disease. It has been proposed that distinct and unrelated proteins（beta-amyloid, tau, α-synuclein, TAR DNA-binding protein 43 and huntingtin, etc.） associated with common neurodegenerative disorders can seed conversion and spread via cellto-cell transfer, sustaining the transmission of neurotoxic agents along a stereotypic route, sharing features at the heart of the intrinsic nature of prions. Here we review the most recent development on both the molecular mechanisms underlying the pathogenesis of prion-like neurodegenerative diseases as well as innovative methods and strategies for potential therapeutic applications.

Assessment of causal effects of physical activity on neurodegenerative diseases:A Mendelian randomization study

Background:Physical activity has been hypothesized to play a protective role in neurodegenerative diseases.However,effect estimates previously derived from observational studies were prone to confounding or reverse causation.Methods:We performed a two-sample Mendelian randomization(MR)analysis to explore the causal association of accelerometer-measured physical activity with 3 common neurodegenerative diseases:Alzheimer’s disease(AD),Parkinson’s disease(PD),and amyotrophic lateral sclerosis(ALS).We selected genetic instrumental variants reaching genome-wide significance(p<5×10^(-8))from 2 largest meta-analyses of about 91,100 UK Biobank participants.Summary statistics for AD,PD,and ALS were retrieved from the up-to-date studies in European ancestry led by the international consortia.The random-effect,inverse-variance weighted MR was employed as the primary method,while MR pleiotropy residual sum and outlier(MR-PRESSO),weighted median,and MR-Egger were implemented as sensitivity tests.All statistical analyses were performed using the R programming language(Version 3.6.1;R Foundation for Statistical Computing,Vienna,Austria).Results:Primary MR analysis and replication analysis utilized 5 and 8 instrumental variables,which explained 0.2%and 0.4%variance in physical activity,respectively.In each set,one variant at 17q21 was significantly associated with PD,and MR sensitivity analyses indicated them it as an outlier and source of heterogeneity and pleiotropy.Primary results with the removal of outlier variants suggested odds ratios(ORs)of neurodegenerative diseases per unit increase in objectively measured physical activity were 1.52 for AD(95%confidence interval(95%CI):0.88-2.63,p=0.13)and 3.35 for PD(95%CI:1.32-8.48,p=0.01),while inconsistent results were shown in the replication set for AD(OR=1.06,95%CI:1.01-1.12,p=0.02)and PD(OR=0.99,95%CI:0.88-0.12,p=0.97).Similarly,the beneficial effect of physical activity on ALS(OR=0.51,95%CI:0.29-0.91,p=0.02)was not confirmed in the replication analysis(OR=0.96,95%CI:0.91-1.02,p=0.22).Conclusion:Genetically predicted physical activity was not robustly associated with risk of neurodegenerative disorders.Triangulating evidence across other studies is necessary in order to elucidate whether enhancing physical activity is an effective approach in preventing the onset of AD,PD,or ALS.

Physiological and pathological functions of circular RNAs in the nervous system

Circular RNAs(circRNAs)are a class of covalently closed single-stranded RNAs that are expressed during the development of specific cells and tissues.CircRNAs play crucial roles in physiological and pathological processes by sponging microRNAs,modulating gene transcription,controlling the activity of certain RNA-binding proteins,and producing functional peptides.A key focus of research at present is the functionality of circRNAs in the nervous system and several advances have emerged over the last 2 years.However,the precise role of circRNAs in the nervous system has yet to be comprehensively reviewed.In this review,we first summarize the recently described roles of circRNAs in brain development,maturity,and aging.Then,we focus on the involvement of circRNAs in various diseases of the central nervous system,such as brain cancer,chronic neurodegenerative diseases,acute injuries of the nervous system,and neuropathic pain.A better understanding of the functionality of circRNAs will help us to develop potential diagnostic,prognostic,and therapeutic strategies to treat diseases of the nervous system.

An Eperimental Study on the Transplantation of Human Fetal Brain Cells into Monkey Models of Parkinson's Disease.

Unilateral administration of methly-phenyl-tetrahydropyridine(MPTP) into the common carotid artery

Neuroimmune interactions and their roles in neurodegenerative diseases

The nervous system possesses bidirectional,sophisticated and delicate communications with the immune system.These neuroimmune interactions play a vitally important role in the initiation and development of many disorders,especially neurodegenerative diseases.Although scientific advancements have made tremendous progress in this field during the last few years,neuroimmune communications are still far from being elucidated.By organizing recent research,in this review,we discuss the local and intersystem neuroimmune interactions and their roles in Alzheimer’s disease,Parkinson’s disease and amyotrophic lateral sclerosis.Unveiling these will help us gain a better understanding of the process of interplay inside the body and how the organism maintains homeostasis.It will also facilitate a view of the diseases from a holistic,pluralistic and interconnected perspective,thus providing a basis of developing novel and effective methods to diagnose,intervene and treat diseases.