Age-related macular degeneration (AMD): Alzheimer's disease in the eye?

Age-related macular degeneration (AMD) is a late-onset, neurodegenerative retinal disease that shares several clinical and pathological features with Alzheimer's disease (AD), including stress stimuli such as oxidative stress and inflammation. In both diseases, the detrimental intra- and extracellular deposits have many similarities. Aging, hypercholesterolaemia, hypertension, obesity, arteriosclerosis, and smoking are risk factors to develop AMD and AD. Cellular aging processes have similar organelle and signaling association in the retina and brain tissues. However, it seems that these diseases have a different genetic background. In this review, differences and similarities of AMD and AD are thoroughly discussed.     

Exons 16 and 17 of the amyloid precursor protein gene in familial inclusion body myopathy

Accumulation of β-amyloid protein (Aβ) occurs in some muscle fibers of patients with inclusion body myopathy and resembles the type of amyloid deposits seen in the affected tissues of patients with Alzheimer's disease and cerebrovascular amyloidosis. Because mutations in exons 16 and 17 of the β-amyloid precursor protein (βAPP) gene on chromosome 21 have been identified in patients with early-onset familial Alzheimer's disease and Dutch-type cerebrovascular amyloidosis, we searched for mutations of the same region in patients with familial inclusion body myopathy. Sequencing of both alleles in 8 patients from four unrelated families did not reveal any mutations in these exons. The amyloid deposition in familial forms of inclusion body myopathy may be either due to errors in other gene loci, or it is secondary reflecting altered βAPP metabolism or myocyte degeneration and cell membrane degradation.     

Age-related macular degeneration is associated with probable cerebral amyloid angiopathy: A case-control study

BackgroundAge-related macular degeneration (AMD) is a common retinal degenerative disorder among older individuals. Amyloid deposits, a hallmark of cerebral amyloid angiopathy (CAA), may be involved in the pathogenesis of AMD. Since amyloid deposits may contribute to the development of both AMD and CAA, we hypothesized that patients with AMD have a higher prevalence of CAA.ObjectiveTo compare the prevalence of CAA in patients with or without AMD matched for age.MethodsWe conducted a cross-sectional, 1:1 age-matched, case-control study of patients ≥40 years of age at the Mayo Clinic who had undergone both retinal optical coherence tomography and brain MRI from 2011 to 2015. Primary dependent variables were probable CAA, superficial siderosis, and lobar and deep cerebral microbleeds (CMBs). The relationship between AMD and CAA was assessed using multivariable logistic regression and was compared across AMD severity (none vs early vs late AMD).ResultsOur analysis included 256 age-matched pairs (AMD 126, no AMD 130). Of those with AMD, 79 (30.9%) had early AMD and 47 (19.4%) had late AMD. The mean age was 75±9 years, and there was no significant difference in vascular risk factors between groups. Patients with AMD had a higher prevalence of CAA (16.7% vs 10.0%, p=0.116) and superficial siderosis (15.1% vs 6.2%, p=0.020), but not deep CMB (5.2% vs 6.2%, p=0.426), compared to those without AMD. After adjusting for covariates, having late AMD was associated with increased odds of CAA (OR 2.83, 95% CI 1.10-7.27, p=0.031) and superficial siderosis (OR 3.40, 95%CI 1.20-9.65, p=0.022), but not deep CMB (OR 0.7, 95%CI 0.14-3.51, p=0.669).ConclusionsAMD was associated with CAA and superficial siderosis but not deep CMB, consistent with the hypothesis that amyloid deposits play a role in the development of AMD. Prospective studies are needed to determine if features of AMD may serve as biomarkers for the early diagnosis of CAA.     

The emerging role of Rab GTPases in the pathogenesis of Parkinson's disease

The identification of pathogenic mutations in Ras analog in brain 39B (RAB39B) and Ras analog in brain 32 (RAB32) that cause Parkinson's disease (PD) has highlighted the emerging role of protein trafficking in disease pathogenesis. Ras analog in brain (Rab) Guanosine triphosphatase (GTPase) function as master regulators of membrane trafficking, including vesicle formation, movement along cytoskeletal networks, and membrane fusion. Recent studies have linked Rab GTPases with α‐synuclein, Leucine‐rich repeat kinase 2, and Vacuolar protein sorting 35, 3 key proteins in PD pathogenesis. In this review, we discuss the various RAB GTPases associated with PD, current progress in the research, and potential future directions. Investigations into the function of RAB GTPases will likely provide significant insight into the etiology of PD and identify novel therapeutic targets for a currently incurable disease. © 2018 International Parkinson and Movement Disorder Society     

Spinocerebellar ataxias: an update

PURPOSE OF REVIEW: Here we discuss recent advances regarding the molecular genetic basis of dominantly inherited ataxias. RECENT FINDINGS: Important recent observations include insights into the mechanisms by which expanded polyglutamine causes cerebellar degeneration; new findings regarding how noncoding expansions may cause disease; the discovery that conventional (i.e. nonrepeat) mutations underlie recently identified ataxias; and growing recognition that multiple biological pathways, when perturbed, can cause cerebellar degeneration. SUMMARY: The dominant ataxias, also known as spinocerebellar ataxias, continue to grow in number. Here we review the major categories of spinocerebellar ataxias: expanded polyglutamine ataxias; noncoding repeat ataxias; and ataxias caused by conventional mutations. After discussing features shared by these disorders, we present recent evidence supporting a toxic protein mechanism for the polyglutamine spinocerebellar ataxias and the recognition that both protein misfolding and perturbations in nuclear events represent key events in pathogenesis. Less is known about pathogenic mechanisms in spinocerebellar ataxias due to noncoding repeats, though a toxic RNA effect remains possible. Newly discovered, conventional mutations in spinocerebellar ataxias suggest a wide range of biological pathways can be disrupted to cause progressive ataxia. Finally, we discuss how new mechanistic insights can drive the push toward preventive treatment.     

The Role of Glucocerebrosidase Mutations in Parkinson Disease and Lewy Body Disorders

Mutations in the gene encoding glucocerebrosidase (GBA), the enzyme deficient in the lysosomal storage disorder Gaucher disease, are associated with the development of Parkinson disease and other Lewy body disorders. In fact, GBA variants are currently the most common genetic risk factor associated with parkinsonism, and identified subjects with Parkinson disease are more than five times more likely to carry mutations in GBA. The mechanisms underlying this association are not known, but proposed theories include enhanced protein aggregation, alterations in lipid levels, and autophagy-lysosomal dysfunction promoting the retention of undegraded proteins. We review the genetic studies linking GBA to parkinsonism, as well as several of the mechanisms postulated to explain the association of GBA mutations and the synucleinopathies, which demonstrate how studies of a rare mendelian disease may provide insights into our understanding of a common complex disorder.     

Leigh syndrome: One disorder,more than 75 monogenic causes

Leigh syndrome is the most common pediatric presentation of mitochondrial disease. This neurodegenerative disorder is genetically heterogeneous, and to date pathogenic mutations in >75 genes have been identified, encoded by 2 genomes (mitochondrial and nuclear). More than one‐third of these disease genes have been characterized in the past 5 years alone, reflecting the significant advances made in understanding its etiological basis. We review the diverse biochemical and genetic etiology of Leigh syndrome and associated clinical, neuroradiological, and metabolic features that can provide clues for diagnosis. We discuss the emergence of genotype–phenotype correlations, insights gleaned into the molecular basis of disease, and available therapeutic options. Ann Neurol 2016;79:190–203     

Autism-associated synaptic mutations impact the gut-brain axis in mice

Interactions between the gut microbiome and the brain affect mood and behaviour in health and disease. Using preclinical animal models, recent discoveries begin to explain how bacteria in the gut influence our mood as well as highlighting new findings relevant to autism. Autism-associated gene mutations known to alter synapse function in the CNS also affect inflammatory response and modify the enteric nervous system resulting in abnormal gastrointestinal motility and structure. Strikingly, these mutations additionally affect the gut microbiome in mice. This review describes the changes in gut physiology and microbiota in mouse models of autism with modified synapse function. The rationale for different regions of the gastrointestinal tract having variable susceptibility to dysfunction is also discussed. To dissect underlying biological mechanisms involving gut-brain axis dysfunction in preclinical models, a range of multidisciplinary approaches are required. This research will provide insights into the role of the gut-brain axis in health and neurodevelopmental disorders including autism.     

Review: insights gained from modelling high-grade glioma in the mouse

High-grade gliomas (HGGs) are devastating primary brain tumours with poor outcomes. Advances towards effective treatments require improved understanding of pathogenesis and relevant model systems for preclinical testing. Mouse models for HGG provide physiologically relevant experimental systems for analysis of HGG pathogenesis. There are advantages and disadvantages to the different methodologies used to generate such models, including implantation, genetic engineering or somatic gene transfer approaches. This review highlights how mouse models have provided insights into the contribution of specific mutations to tumour initiation, progression and phenotype, the influence of tumour micro-environment, and the analysis of cell types that can give rise to glioma. HGGs are a heterogeneous group of tumours, and the complexity of diverse mutations within common signalling pathways as well as the developmental and cell-type context of transformation contributes to the overall diversity of glioma phenotype. Enhanced understanding of the mutations and cell types giving rise to HGG, along with the ability to design increasingly complex mouse models that more closely simulate the process of human gliomagenesis will continue to provide improved experimental systems for dissecting mechanisms of disease pathogenesis and for preclinical testing.     

A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis

The amyloid hypothesis has dominated the thinking in our attempts to understand, diagnose and develop drugs for Alzheimer's disease (AD). This article presents a new hypothesis that takes into account the numerous familial AD (FAD) mutations in the amyloid precursor protein (APP) and its processing pathways, but suggests a new perspective beyond toxicity of forms of the amyloid beta-peptide (Abeta). Clearly, amyloid deposits are an invariable feature of AD. Moreover, although APP is normally processed to secreted and membrane-bound fragments, sAPPbeta and CTFbeta, by BACE, and the latter is subsequently processed by gamma-secretase to Abeta and CTFgamma, this pathway mostly yields Abeta of 40 residues, and increases in the levels of the amyloidogenic 42-residue Abeta (Abeta42) are seen in the majority of the mutations linked to the disease. The resulting theory is that the disease is caused by amyloid toxicity, which impairs memory and triggers deposition of the microtubule associated protein, Tau, as neurofibrillary tangles. Nevertheless, a few exceptional FAD mutations and the presence of large amounts of amyloid deposits in a group of cognitively normal elderly patients suggest that the disease process is more complex. Indeed, it has been hard to demonstrate the toxicity of Abeta42 and the actual target has been shifted to small oligomers of the peptide, named Abeta derived diffusible ligands (ADDLs). Our hypothesis is that the disease is more complex and caused by a failure of APP metabolism or clearance, which simultaneously affects several other membrane proteins. Thus, a traffic jam is created by failure of important pathways such as gamma-secretase processing of residual intramembrane domains released from the metabolism of multiple membrane proteins, which ultimately leads to a multiple system failure. In this theory, toxicity of Abeta42 will only contribute partially, if at all, to neurodegeneration in AD. More significantly, this theory would predict that focussing on specific reagents such as gamma-secretase inhibitors that hamper metabolism of APP, may initially show some beneficial effects on cognitive performance by elimination of acutely toxic ADDLs, but over the longer term may exacerbate the disease process by reducing membrane protein turnover.     

Factor V Leiden mutation is associated with enhanced arterial thrombotic tendency in lean but not in obese mice

The homozygous factor V Leiden mutation is associated with enhanced venous thrombotic risk. Obesity is a major risk factor for development of thrombotic cardiovascular disease. It was the objective of this study to investigate whether obesity affects the thrombotic risk associated with the mutation. Male mice with homozygous factor V Leiden mutation (Arg 504 to Gln) (FVQ/Q) and corresponding wild-type (WT) mice were kept on a standard fat diet (SFD) or high fat diet (HFD) for 14 weeks, and femoral artery thrombosis was induced by FeCl3 treatment. As compared to SFD, HFD feeding for 14 weeks resulted in significantly higher body weight and fat mass associated with adipocyte hypertrophy, which were, however, similar for both genotypes. In the FeCl3-induced arterial thrombosis model, FVQ/Q mice kept on SFD had a 40% shorter occlusion time (p = 0.015) and 40% lower blood flow (p = 0.03), as compared to WT mice. However, on HFD the occlusion time and blood flow were not significantly different for both genotypes. This finding could not be explained by differential changes of coagulation factors in either genotype fed on SFD or HFD. In conclusion, on SFD, but not on HFD, the factor V Leiden mutation is associated with enhanced thrombotic tendency after FeCl3 injury of the femoral artery, suggesting that in this model obesity rescues the increased thrombotic risk associated with the factor V Leiden mutation.     

Differential expression of matrix metalloproteinases in monkey eyes with experimental glaucoma or optic nerve transection

Extracellular matrix (ECM) remodeling after neuronal injury and reactive gliosis is carried out by activation of matrix metalloproteinases (MMPs) regulated by their tissue inhibitors (TIMPs). In glaucoma, there is a loss of retinal ganglion cells and extensive ECM remodeling (cupping) at the level of the optic nerve head, frequently associated with elevated intraocular pressure. To determine whether ECM remodeling in the glaucomatous optic nerve head occurs in response to loss of axons or to elevated intraocular pressure we compared the patterns of MMP and TIMP expression in the eyes of monkeys with laser-induced glaucoma or with optic nerve transection. MT1-MMP and MMP1 expression was markedly increased in reactive astrocytes in optic nerve heads with experimental glaucoma but not in the optic nerve head of transected eyes. In normal control eyes retinal ganglion cells expressed MMP2, TIMP1 and TIMP2 constitutively, and the proteins were detected in their axons. At the site of transection, MT1-MMP, MMP1, MMP2, TIMP1 and TIMP2 were expressed by reactive astrocytes. Inflammatory cells, fibroblasts and reactive astrocytes at the transected site expressed MMP3 and MMP9, which were undetectable in the retina and optic nerve head in any condition. Constitutive expression of MMP2, TIMP1 and TIMP2 in retinal ganglion cells suggests a role in maintenance of synaptic integrity and plasticity and maintenance of the periaxonal space. Increased MMP1 and MT1-MMP1 expression in the glaucomatous optic nerve head is specific to tissue remodeling due to elevated intraocular pressure and not secondary to loss of axons.     

Trauma experience in individuals with idiopathic environmental intolerance and individuals with somatoform disorders

OBJECTIVE: Results from previous studies suggest that past trauma experience increases the risk for medically unexplained somatic symptoms and somatoform disorders (SFD). This cross-sectional study examined the link between various lifetime traumas, idiopathic environmental intolerance (IEI), and SFD. METHODS: Two clinical groups of 54 subjects with IEI and 44 subjects with SFD were compared to 54 subjects (comparison group, CG) free from both IEI and SFD regarding self-reported traumas. The subjects were mainly recruited via advertisements in local newspapers. From 970 individuals screened for IEI and multiple somatic symptoms, 152 were included through a two-step selection procedure consisting of screening questionnaires, a medical examination, and structured interviews for IEI and mental disorders. RESULTS: In all three groups at least one potential traumatic event was reported rather frequently (CG: 70%; IEI: 82%; SFD: 73%). But contrary to our expectation, significant group differences were neither found in regard to the proportion of subjects with any trauma, nor traumas fulfilling DSM-IV criteria (CG: 41%; IEI: 48%; SFD: 59%), nor multiple traumas (CG: 43%, IEI: 56%, SFD: 39%). Only two trauma categories were endorsed more frequently by the two clinical groups than by the CG: the unspecified 'other' category (IEI, SFD>CG) and 'life-threatening illness' (IEI>CG). CONCLUSION: No clear evidence was found for increased rates of trauma experience in IEI and SFD. However, the results of this exploratory study should be considered as preliminary. Comparing larger IEI and SFD groups with a representative population-based sample may yield different results.     

生物羊膜与新鲜羊膜移植治疗早期眼烧伤的比较

摘要 背景：羊膜移植目前已普遍应用于眼表重建，给早期眼烧伤患者的治疗提供了新的手段。但是羊膜的选择目前还没有统一标准，临床效果的报道也有部分差异。 目的：新鲜羊膜与生物羊膜移植治疗早期眼烧伤的疗效比较。 方法：收集66例(66眼)早期眼烧伤患者，随机分为新鲜羊膜组和生物羊膜组，每组33例，分别采用新鲜羊膜移植和生物羊膜移植治疗。术后随访3个月，观察并比较两组视力、植片成活、并发症发生情况。 结果与结论：两组术后视力较术前均有明显提高，差异有显著性意义(P < 0.05)；新鲜羊膜组和生物羊膜组分别有2例和3例出现羊膜早溶和脱落，经二次羊膜移植后均获成功。两组角膜白斑、角膜斑翳和角膜新生血管等并发症发生情况比较差异无显著性意义(P > 0.05)。结果表明新鲜羊膜与生物羊膜均可有效治疗早期眼表烧伤，重建眼表，二者疗效比较无显著性差异。 关键词：新鲜羊膜；生物羊膜；眼表；化学性烧伤；移植 doi:10.3969/j.issn.1673-8225.2010.47.039     

Becker’s myotonia: novel mutations and clinical variability in patients born to consanguineous parents

Myotonia congenita is an inherited muscle disease present from childhood that is characterized by impaired muscle relaxation after contraction resulting in muscle stiffness; moreover, skeletal striated muscle groups may be involved. Myotonia congenita occurs due to chloride (Cl) channel mutations that reduce the stabilizing Cl conductance, and it is caused by mutations in the CLCN1 gene. This paper describes four patients from two different healthy consanguineous Turkish families with muscle stiffness and easy fatigability. A genetic investigation was performed. Mutation analyses showed a homozygous p.Tyr150* (c.450C > A) mutation in patients 1, 2 and 3 and a homozygous p.Leu159Cysfs*11 (c.475delC) mutation in patient 4 in the CLCN1 gene. These mutations have never been reported before and in silico analyses showed that the mutations were disease causing. They may be predicted to cause nonsense-mediated mRNA decay. Our data expand the spectrum of CLCN1 mutations and provide insights for genotype–phenotype correlations of myotonia congenita.     

Novel Insights into the Pathomechanisms of Skeletal Muscle Channelopathies

The nondystrophic myotonias and primary periodic paralyses are an important group of genetic muscle diseases characterized by dysfunction of ion channels that regulate membrane excitability. Clinical manifestations vary and include myotonia, hyperkalemic and hypokalemic periodic paralysis, progressive myopathy, and cardiac arrhythmias. The severity of myotonia ranges from severe neonatal presentation causing respiratory compromise through to mild later-onset disease. It remains unclear why the frequency of attacks of paralysis varies greatly or why many patients develop a severe permanent fixed myopathy. Recent detailed characterizations of human genetic mutations in voltage-gated muscle sodium (gene: SCN4A), chloride (gene: CLCN1), calcium (gene: CACNA1S), and inward rectifier potassium (genes: KCNJ2, KCNJ18) channels have resulted in new insights into disease mechanisms, clinical phenotypic variation, and therapeutic options     

The complexities underlying age-related macular degeneration: could amyloid beta play an important role?

Age-related macular degeneration(AMD) causes irreversible loss of central vision for which there is no effective treatment. Incipient pathology is thought to occur in the retina for many years before AMD manifests from midlife onwards to affect a large proportion of the elderly. Although genetic as well as non-genetic/environmental risks are recognized, its complex aetiology makes it difficult to identify susceptibility, or indeed what type of AMD develops or how quickly it progresses in different individuals. Here we summarize the literature describing how the Alzheimer's-linked amyloid beta(Aβ) group of misfolding proteins accumulate in the retina. The discovery of this key driver of Alzheimer's disease in the senescent retina was unexpected and surprising, enabling an altogether different perspective of AMD. We argue that Aβ fundamentally differs from other substances which accumulate in the ageing retina, and discuss our latest findings from a mouse model in which physiological amounts of Aβ were subretinally-injected to recapitulate salient features of early AMD within a short period. Our discoveries as well as those of others suggest the pattern of Aβ accumulation and pathology in donor aged/AMD tissues are closely reproduced in mice, including late-stage AMD phenotypes, which makes them highly attractive to study dynamic aspects of Aβ-mediated retinopathy. Furthermore, we discuss our findings revealing how Aβ behaves at single-cell resolution, and consider the long-term implications for neuroretinal function. We propose Aβ as a key element in switching to a diseased retinal phenotype, which is now being used as a biomarker for latestage AMD.     

Molecular genetics of familial parkinsonism

Parkinson's disease (PD) is a progressive, neurodegenerative disorder associated with tremor, rigidity, bradykinesia, and postural instability. There exists a familial form of PD that is indistinguishable from the sporadic form. In addition, there exists a class of syndromes classified as parkinsonism-plus syndromes (PPS), in which parkinsonism is an essential but not the only phenotypic characteristic. The etiology of PD remains unclear. Both environmental and genetic factors contribute to the disease pathogenesis. Recent progress in the molecular genetics of parkinsonism has demonstrated that six different chromosomal regions are associated with forms of familial parkinsonism. Mutations in four candidate genes have been identified and include both point mutations and deletions. Both gain-of-function and loss-of-function mutational mechanisms have been implicated. The molecular genetic characterization has led to a new classification of PD and PPS based on the type of genetic defect. Understanding the mechanisms by which these mutations lead to disease should provide further insights into the etiology of parkinsonism.     

Blood clotting reactions on nanoscale phospholipid bilayers

Blood clotting reactions, such as those catalyzed by the tissue factor:factor VIIa complex (TF:FVIIa), assemble on membrane surfaces containing anionic phospholipids such as phosphatidylserine (PS). In fact, membrane binding is critical for the function of most of the steps in the blood clotting cascade. In spite of this, our understanding of how the membrane contributes to catalysis, or even how these proteins interact with phospholipids, is incomplete. Making matters more complicated, membranes containing mixtures of PS and neutral phospholipids are known to spontaneously form PS-rich membrane microdomains in the presence of plasma concentrations of calcium ions, and it is likely that blood-clotting proteases such as TF:FVIIa partition into these PS-rich microdomains. Unfortunately, little is known about how membrane microdomain composition influences the activity of blood-clotting proteases, which is typically not under experimental control even in "simple" model membranes. Our laboratories have developed and applied new technologies for studying membrane proteins to gain insights into how blood-clotting protease-cofactor pairs assemble and function on membrane surfaces. This includes using a novel, nanoscale bilayer system (Nanodiscs) that permits assembling blood-clotting protease-cofactor pairs on stable bilayers containing from 65 to 250 phospholipid molecules per leaflet. We have used this system to investigate how local (nanometer-scale) changes in phospholipid bilayer composition modulate TF:FVIIa activity. We have also used detailed molecular-dynamics simulations of nanoscale bilayers to provide atomic-scale predictions of how the membrane-binding domain of factor VIIa interacts with PS in membranes.