Eph receptors at synapses: implications in neurodegenerative diseases

Precise regulation of synapse formation, maintenance and plasticity is crucial for normal cognitive function, and synaptic failure has been suggested as one of the hallmarks of neurodegenerative diseases. In this review, we describe the recent progress in our understanding of how the receptor tyrosine kinase Ephs and their ligands ephrins regulate dendritic spine morphogenesis, synapse formation and maturation, as well as synaptic plasticity. In particular, we discuss the emerging evidence implicating that deregulation of Eph/ephrin signaling contributes to the aberrant synaptic functions associated with cognitive impairment in Alzheimer's disease. Understanding how Eph/ephrin regulates synaptic function may therefore provide new insights into the development of therapeutic agents against neurodegenerative diseases.     

Oligodendrocytes in neurodegenerative diseases

Oligodendrocyte is a highly specialized glial cell type in the vertebrate central nervous system, which guarantees the long-distance transmission of action potential by producing myelin sheath wrapping adjacent axons. Disrupted myelin and oligodendrocytes are hallmarks of some devastating neurological diseases, such as multiple sclerosis, although their contribution to neurodegeneration in a given disease is still controversial. However, accumulating evidence from clinical studies and genetic animal models implicates oligodendrocyte dysfunction as one of major events in the processes of initiation and progression of neurodegeneration. In this article, we will review recent progress in understanding non-traditional function of oligodendrocytes in neuronal support and protection independent of myelin sheath and its possible contribution to neurodegeneration. Oligodendrocytes play a pivotal role in neurodegenerative diseases among which special emphasis is given to multiple system atrophy and Alzheimer’s disease in this review.     

Proteomics in neurodegenerative diseases

The effects of amyloid-beta (Aβ) protein on the expression of m1, m2 subunits of mAChR and on α7nAChR were analyzed in the cerebral cortex and in the hippocampus of rats following injections of Aβ (1–40) (BACHEM, 2 μg in 1 μL of PBS) into the left retroesplenial cortex (RSg) and injections of 1 μL of PBS into the right RSg. Sections were immunoreacted for the localization of α7, m1, m2, GABA, somatostatin and parvalbumin. Injections of Aβ resulted in loss of neurones expressing α7- and m1-like immunoreactivity (IR) in frontal, RSg cortices, hippocampus and subicular complex. A decrease of α7, m1- and m2-like-IR fibers and structures-like terminals was also seen in hippocampus, subicular and cerebral cortex. α7nAChR and m1, m2 subuntis of mAChRs were most commonly identified on GABAergic interneurones. These results point to an effect of Aβ on the synthesis of α7nAChR and mAChRs and suggest an important role of cholinoceptive interneurones in the dysfunction of hippocampus and cerebral cortex seen in AD.     

Age at the onset of senescence in birds and mammals is predicted by early-life performance

Life-history theory predicts that traits involved in maturity, reproduction and survival correlate along a fast–slow continuum of life histories. Evolutionary theories and empirical results indicate that senescence-related traits vary along this continuum, with slow species senescing later and at a slower pace than fast species. Because senescence patterns are typically difficult to estimate from studies in the wild, here we propose to predict the associated trait values in the frame of life-history theory. From a comparative analysis based on 81 free-ranging populations of 72 species of birds and mammals, we find that a nonlinear combination of fecundity, age at first reproduction and survival over the immature stage can account for ca two-thirds of the variance in the age at the onset of actuarial senescence. Our life-history model performs better than a model predicting the onset based on generation time, and it only includes life-history traits during early life as explanatory variables, i.e. parameters that are both theoretically expected to shape senescence and are measurable within relatively short studies. We discuss the good-fit of our life-history model to the available data in the light of current evolutionary theories of senescence. We further use it to evaluate whether studies that provided no evidence for senescence lasted long enough to include the onset of senescence.     

Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases

Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer''s disease (AD) and Huntington''s disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10⁻¹²), while Dnmt3a KO signature does not (P = 0.017).     

Metal imaging in neurodegenerative diseases

Metal ions are known to play an important role in many neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and prion diseases. In these diseases, aberrant metal binding or improper regulation of redox active metal ions can induce oxidative stress by producing cytotoxic reactive oxygen species (ROS). Altered metal homeostasis is also frequently seen in the diseased state. As a result, the imaging of metals in intact biological cells and tissues has been very important for understanding the role of metals in neurodegenerative diseases. A wide range of imaging techniques have been utilized, including X-ray fluorescence microscopy (XFM), particle induced X-ray emission (PIXE), energy dispersive X-ray spectroscopy (EDS), laser ablation inductively coupled mass spectrometry (LA-ICP-MS), and secondary ion mass spectrometry (SIMS), all of which allow for the imaging of metals in biological specimens with high spatial resolution and detection sensitivity. These techniques represent unique tools for advancing the understanding of the disease mechanisms and for identifying possible targets for developing treatments. In this review, we will highlight the advances in neurodegenerative disease research facilitated by metal imaging techniques.     

Tau mutations in neurodegenerative diseases

Tau deposition is found in a variety of neurodegenerative brain diseases. The identification of tau mutations that cause familial dementia demonstrated that aberrant Tau alone could cause neurodegenerative disease and suggested that Tau likely plays a role in other cases in which Tau deposits are found, most notably Alzheimer disease. The mechanisms by which tau mutations cause neurodegeneration vary and are unclear to some degree, but evidence supports changes in alternative splicing, phosphorylation state, interaction with tubulin, and self-association into filaments as important contributing factors.     

Legionella pneumophila growth in macrophages from susceptible mice is genetically controlled

Growth of the intracellular opportunistic bacterium Legionella pneumophila in macrophages from A/J mice is a vigorous as growth in macrophages from susceptible guinea pigs and human monocytes, whereas growth is inhibited in macrophages from other mouse strains, such as nonpermissive BALB/c mice. Permissiveness versus nonpermissiveness of macrophages from A/J versus BALB/c mice appeared to be controlled by a genetic mechanism dependent upon a single gene or a closely clustered family of genes. Susceptibility versus resistance of macrophages from F1 offspring of these two strains of mice and macrophages from backcrossed mice prepared from F1 hybrids and the original parental strain showed a segregation of permissiveness for growth of Legionella in vitro, consistent with genetic control.     

The two faces of protein misfolding: gain- and loss-of-function in neurodegenerative diseases

The etiologies of neurodegenerative diseases may be diverse; however, a common pathological denominator is the formation of aberrant protein conformers and the occurrence of pathognomonic proteinaceous deposits. Different approaches coming from neuropathology, genetics, animal modeling and biophysics have established a crucial role of protein misfolding in the pathogenic process. However, there is an ongoing debate about the nature of the harmful proteinaceous species and how toxic conformers selectively damage neuronal populations. Increasing evidence indicates that soluble oligomers are associated with early pathological alterations, and strikingly, oligomeric assemblies of different disease-associated proteins may share common structural features. A major step towards the understanding of mechanisms implicated in neuronal degeneration is the identification of genes, which are responsible for familial variants of neurodegenerative diseases. Studies based on these disease-associated genes illuminated the two faces of protein misfolding in neurodegeneration: a gain of toxic function and a loss of physiological function, which can even occur in combination. Here, we summarize how these two faces of protein misfolding contribute to the pathomechanisms of Alzheimer's disease, frontotemporal lobar degeneration, Parkinson's disease and prion diseases.     

Gene therapy strategies in neurodegenerative diseases

Treatment of neurodegenerative diseases by classical pharmacotherapy is restricted by blood-brain barrier which prevents access to the brain of potentially therapeutic molecules. Recent progress in the knowledge of pathophysiological molecular processes, and in the development of molecular biotechnology have opened the way to new therapeutic interventions for these disorders. This chapter reviews the most recent gene therapy strategies using experimental models for neurodegenerative diseases.     

High content screening in neurodegenerative diseases

The functional annotation of genomes, construction of molecular networks and novel drug target identification, are important challenges that need to be addressed as a matter of great urgency. Multiple complementary 'omics' approaches have provided clues as to the genetic risk factors and pathogenic mechanisms underlying numerous neurodegenerative diseases, but most findings still require functional validation. For example, a recent genome wide association study for Parkinson's Disease (PD), identified many new loci as risk factors for the disease, but the underlying causative variant(s) or pathogenic mechanism is not known. As each associated region can contain several genes, the functional evaluation of each of the genes on phenotypes associated with the disease, using traditional cell biology techniques would take too long. There is also a need to understand the molecular networks that link genetic mutations to the phenotypes they cause. It is expected that disease phenotypes are the result of multiple interactions that have been disrupted. Reconstruction of these networks using traditional molecular methods would be time consuming. Moreover, network predictions from independent studies of individual components, the reductionism approach, will probably underestimate the network complexity. This underestimation could, in part, explain the low success rate of drug approval due to undesirable or toxic side effects. Gaining a network perspective of disease related pathways using HT/HC cellular screening approaches, and identifying key nodes within these pathways, could lead to the identification of targets that are more suited for therapeutic intervention. High-throughput screening (HTS) is an ideal methodology to address these issues. but traditional methods were one dimensional whole-well cell assays, that used simplistic readouts for complex biological processes. They were unable to simultaneously quantify the many phenotypes observed in neurodegenerative diseases such as axonal transport deficits or alterations in morphology properties. This approach could not be used to investigate the dynamic nature of cellular processes or pathogenic events that occur in a subset of cells. To quantify such features one has to move to multi-dimensional phenotypes termed high-content screening (HCS). HCS is the cell-based quantification of several processes simultaneously, which provides a more detailed representation of the cellular response to various perturbations compared to HTS. HCS has many advantages over HTS, but conducting a high-throughput (HT)-high-content (HC) screen in neuronal models is problematic due to high cost, environmental variation and human error. In order to detect cellular responses on a 'phenomics' scale using HC imaging one has to reduce variation and error, while increasing sensitivity and reproducibility. Herein we describe a method to accurately and reliably conduct shRNA screens using automated cell culturing and HC imaging in neuronal cellular models. We describe how we have used this methodology to identify modulators for one particular protein, DJ1, which when mutated causes autosomal recessive parkinsonism. Combining the versatility of HC imaging with HT methods, it is possible to accurately quantify a plethora of phenotypes. This could subsequently be utilized to advance our understanding of the genome, the pathways involved in disease pathogenesis as well as identify potential therapeutic targets.     

Role of manganese in neurodegenerative diseases

Manganese (Mn) is an essential ubiquitous trace element that is required for normal growth, development and cellular homeostasis. Exposure to high Mn levels causes a clinical disease characterized by extrapyramidal symptom resembling idiopathic Parkinson's disease (IPD). The present review focuses on the role of various transporters in maintaining brain Mn homeostasis along with recent methodological advances in real-time measurements of intracellular Mn levels. We also provide an overview on the role for Mn in IPD, discussing the similarities (and differences) between manganism and IPD, and the relationship between α-synuclein and Mn-related protein aggregation, as well as mitochondrial dysfunction, Mn and PD. Additional sections of the review discuss the link between Mn and Huntington's disease (HD), with emphasis on huntingtin function and the potential role for altered Mn homeostasis and toxicity in HD. We conclude with a brief survey on the potential role of Mn in the etiologies of Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS) and prion disease. Where possible, we discuss the mechanistic commonalities inherent to Mn-induced neurotoxicity and neurodegenerative disorders.     

小胶质细胞与炎症介导的神经系统退行性病变

小胶质细胞是中枢神经系统常驻细胞,行使支持、营养、免疫监视等多种功能。小胶质细胞在受到感染、外伤等因素刺激后活化,并产生多种免疫效应分子,包括：白细胞介素、肿瘤坏死因子、干扰素γ、活性氮、活性氧等。这些因子介导慢性炎症反应、细胞凋亡等,是导致神经系统退行性病变的主要因素。本文着重阐述小胶质细胞通过分泌这些效应分子引起神经功能损伤的机制,并对目前一些针对性治疗方法加以介绍。     

Abnormal tau-containing filaments in neurodegenerative diseases

It has been known for some time that the neurofibrillary pathology in Alzheimer's disease consists of so-called paired helical and straight filaments made up of the microtubule-associated protein tau. The degree of dementia observed in the disease correlates better with the extent of neurofibrillary pathology than with the Abeta amyloid deposits, the other characteristic defining pathological fibrous deposit in Alzheimer's disease. However, no familial cases of Alzheimer's disease have been genetically linked to the tau protein locus. Recently a group of frontotemporal dementias with parkinsonism linked to chromosome 17 has been shown to be caused by mutations in the tau gene. Some are missense mutations giving altered tau proteins, whereas others affect the splicing of the pre-mRNA and change the balance between different tau isoforms. Histologically these diseases are all characterised by various kinds of filamentous tau protein deposits, mostly in the complete absence of Abeta deposits. The abnormal tau filaments show different morphologies, depending on the nature of the tau mutation. These diseases show that tau mutations can be a prime cause of inherited dementing illness and may throw some light on the pathological process in the much larger number of sporadic cases of Alzheimer's disease.     

New insights into the role of microRNAs and long noncoding RNAs in most common neurodegenerative diseases

Neurodegenerative diseases (NDs) are a diversity of neurological disorders characterized by the progressive degeneration of the structure and function of the central nervous system (CNS). The most common NDs are Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, many studies have investigated associations between common NDs with noncoding RNAs (ncRNAs) molecules. ncRNAs are regulatory molecules in the normal functioning of the CNS. Two of the most important ncRNAs are microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). These types of ncRNAs are involved in different biological processes including brain development, maturation, differentiation, neuronal cell specification, neurogenesis, and neurotransmission. Increasing data has demonstrated that miRNAs and lncRNAs have strong correlations with the development of NDs, particularly gene expression. Besides, ncRNAs can be introduced as new biomarkers for diagnosis and prognosis of NDs. Hence, in this review, we summarized the involvement of various miRNAs and lncRNAs in most common NDs followed by a correlation of ncRNAs dysregulation with the AD, PD, and HD.     

Extensive natural variation for cellular hydrogen peroxide release is genetically controlled

Natural variation in DNA sequence contributes to individual differences in quantitative traits. While multiple studies have shown genetic control over gene expression variation, few additional cellular traits have been investigated. Here, we investigated the natural variation of NADPH oxidase-dependent hydrogen peroxide (H₂O₂ release), which is the joint effect of reactive oxygen species (ROS) production, superoxide metabolism and degradation, and is related to a number of human disorders. We assessed the normal variation of H₂O₂ release in lymphoblastoid cell lines (LCL) in a family-based 3-generation cohort (CEPH-HapMap), and in 3 population-based cohorts (KORA, GenCord, HapMap). Substantial individual variation was observed, 45% of which were associated with heritability in the CEPH-HapMap cohort. We identified 2 genome-wide significant loci of Hsa12 and Hsa15 in genome-wide linkage analysis. Next, we performed genome-wide association study (GWAS) for the combined KORA-GenCord cohorts (n = 279) using enhanced marker resolution by imputation (>1.4 million SNPs). We found 5 significant associations (p<5.00×10−8) and 54 suggestive associations (p<1.00×10−5), one of which confirmed the linked region on Hsa15. To replicate our findings, we performed GWAS using 58 HapMap individuals and ∼2.1 million SNPs. We identified 40 genome-wide significant and 302 suggestive SNPs, and confirmed genome signals on Hsa1, Hsa12, and Hsa15. Genetic loci within 900 kb from the known candidate gene p67phox on Hsa1 were identified in GWAS in both cohorts. We did not find replication of SNPs across all cohorts, but replication within the same genomic region. Finally, a highly significant decrease in H₂O₂ release was observed in Down Syndrome (DS) individuals (p<2.88×10−12). Taken together, our results show strong evidence of genetic control of H₂O₂ in LCL of healthy and DS cohorts and suggest that cellular phenotypes, which themselves are also complex, may be used as proxies for dissection of complex disorders.     

A genetically controlled lactate dehydrogenase variant at the B locus in mink

Erythrocytes of 119 mink, and tissue extracts of three mink, were examined for electrophoretic patterns of lactate dehydrogenase (LDH). A variant was detected at the B locus. There are two alleles, LDH-B ^a and LDH-B ^b; three phenotypes, LDH-Ba, LDH-Bab, and LDH-Bb; and three genotypes, LDH-B ^a/LDH-B^a, LDH-B^a/LDH-B^b, and LDH-B ^b/LDH-B^b. The inheritance as observed in 24 families agrees with an autosomal, codominant, two-allele system at the LDH B locus.Supported by National Research Council Grant A-4442 and the Ontario Department of Agriculture and Food.