scholarly journals Systems pathology analysis identifies neurodegenerative nature of age-related retinal diseases

2018 ◽  
Author(s):  
Tiina Öhman ◽  
Fitsum Tamene ◽  
Helka Göös ◽  
Sirpa Loukovaara ◽  
Markku Varjosalo
Keyword(s):  
Molecular Mechanisms ◽  
System Development ◽  
Fibrous Tissue ◽  
Nervous System Development ◽  
Public Health Issue ◽  
Retinal Diseases ◽  
Label Free ◽  
Systems Pathology ◽  
Age Related ◽  
Vitreoretinal Diseases

AbstractAging is a phenomenon associated with profound medical implications. Idiopathic epiretinal membrane (iEMR) and macular hole (MH) are the major vision-threatening vitreoretinal diseases affecting millions of aging people globally, making these conditions an important public health issue. The iERM is characterized by fibrous tissue developing on the surface of the macula, leading to biomechanical and biochemical macular damage. MH is a small breakage in the macula associated with many ocular conditions. Although several individual factors and pathways are suggested, a systems pathology level understanding of the molecular mechanisms underlying these disorders is lacking. Therefore, we performed mass spectrometry based label-free quantitative proteomics analysis of the vitreous proteomes from patients with iERM (n=26) and MH (n=21) to identify the key proteins as well as the multiple interconnected biochemical pathways contributing to the development of these diseases. We identified a total of 1014 unique proteins, of which many were linked to inflammation and complement cascade, revealing the inflammational processes in retinal diseases. Additionally, we detected a profound difference in proteomes of the iEMR and MH compared to the non-proliferative diabetic retinopathy. A large number of neuronal proteins were present at higher levels in iERM and MH vitreous, including neuronal adhesion molecules, nervous system development proteins and signalling molecules. This points toward the important role of neurodegeneration component in the pathogenesis of age-related vitreoretinal diseases. Despite of marked similarities, several unique vitreous proteins were identified in both iERM and MH conditions, providing a candidate targets for diagnostic and new therapeutic approaches. Identification of previously reported and novel proteins in human vitreous humor from patient with iERM and MH provide renewed understanding of the pathogenesis of age-related vitreoretinal diseases.

scholarly journals Zebrafish Models of Autosomal Recessive Ataxias

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 836
Author(s):  
Ana Quelle-Regaldie ◽  
Daniel Sobrido-Cameán ◽  
Antón Barreiro-Iglesias ◽  
María Jesús Sobrido ◽  
Laura Sánchez
Keyword(s):  
Animal Models ◽  
Autosomal Recessive ◽  
Molecular Mechanisms ◽  
System Development ◽  
Rapid Development ◽  
Nervous System Development ◽  
Central Nervous System Development ◽  
Cellular Processes ◽  
Recessive Disorders

Autosomal recessive ataxias are much less well studied than autosomal dominant ataxias and there are no clearly defined systems to classify them. Autosomal recessive ataxias, which are characterized by neuronal and multisystemic features, have significant overlapping symptoms with other complex multisystemic recessive disorders. The generation of animal models of neurodegenerative disorders increases our knowledge of their cellular and molecular mechanisms and helps in the search for new therapies. Among animal models, the zebrafish, which shares 70% of its genome with humans, offer the advantages of being small in size and demonstrating rapid development, making them optimal for high throughput drug and genetic screening. Furthermore, embryo and larval transparency allows to visualize cellular processes and central nervous system development in vivo. In this review, we discuss the contributions of zebrafish models to the study of autosomal recessive ataxias characteristic phenotypes, behavior, and gene function, in addition to commenting on possible treatments found in these models. Most of the zebrafish models generated to date recapitulate the main features of recessive ataxias.

Environment and Brain Plasticity: Towards an Endogenous Pharmacotherapy

2014 ◽  
Vol 94 (1) ◽  
pp. 189-234 ◽  
Author(s):  
Alessandro Sale ◽  
Nicoletta Berardi ◽  
Lamberto Maffei
Keyword(s):  
Environmental Enrichment ◽  
Molecular Mechanisms ◽  
Brain Plasticity ◽  
System Development ◽  
Basic Research ◽  
Nervous System Development ◽  
Adult Brain ◽  
Aging Brain ◽  
Cerebral Neurons ◽  
And Function

Brain plasticity refers to the remarkable property of cerebral neurons to change their structure and function in response to experience, a fundamental theoretical theme in the field of basic research and a major focus for neural rehabilitation following brain disease. While much of the early work on this topic was based on deprivation approaches relying on sensory experience reduction procedures, major advances have been recently obtained using the conceptually opposite paradigm of environmental enrichment, whereby an enhanced stimulation is provided at multiple cognitive, sensory, social, and motor levels. In this survey, we aim to review past and recent work concerning the influence exerted by the environment on brain plasticity processes, with special emphasis on the underlying cellular and molecular mechanisms and starting from experimental work on animal models to move to highly relevant work performed in humans. We will initiate introducing the concept of brain plasticity and describing classic paradigmatic examples to illustrate how changes at the level of neuronal properties can ultimately affect and direct key perceptual and behavioral outputs. Then, we describe the remarkable effects elicited by early stressful conditions, maternal care, and preweaning enrichment on central nervous system development, with a separate section focusing on neurodevelopmental disorders. A specific section is dedicated to the striking ability of environmental enrichment and physical exercise to empower adult brain plasticity. Finally, we analyze in the last section the ever-increasing available knowledge on the effects elicited by enriched living conditions on physiological and pathological aging brain processes.

scholarly journals Regulation of Gliogenesis by lin-32/Atoh1 in Caenorhabditis elegans

2020 ◽  
Vol 10 (9) ◽  
pp. 3271-3278 ◽  
Author(s):  
Albert Zhang ◽  
Kentaro Noma ◽  
Dong Yan
Keyword(s):  
Nervous System ◽  
Caenorhabditis Elegans ◽  
Embryonic Development ◽  
Molecular Mechanisms ◽  
System Development ◽  
Nervous System Development ◽  
Proneural Gene ◽  
C Elegans ◽  
Fundamental Process ◽  
Mutant Phenotypes

Abstract The regulation of gliogenesis is a fundamental process for nervous system development, as the appropriate glial number and identity is required for a functional nervous system. To investigate the molecular mechanisms involved in gliogenesis, we used C. elegans as a model and identified the function of the proneural gene lin-32/Atoh1 in gliogenesis. We found that lin-32 functions during embryonic development to negatively regulate the number of AMsh glia. The ectopic AMsh cells at least partially arise from cells originally fated to become CEPsh glia, suggesting that lin-32 is involved in the specification of specific glial subtypes. Moreover, we show that lin-32 acts in parallel with cnd-1/ NeuroD1 and ngn-1/ Neurog1 in negatively regulating an AMsh glia fate. Furthermore, expression of murine Atoh1 fully rescues lin-32 mutant phenotypes, suggesting lin-32/Atoh1 may have a conserved role in glial specification.

No pun intended: future directions in invertebrate glial cell migration studies

2007 ◽  
Vol 3 (1) ◽  
pp. 45-54 ◽  
Author(s):  
Patrick Cafferty ◽  
Vanessa J. Auld
Keyword(s):  
Nervous System ◽  
Cell Migration ◽  
Glial Cell ◽  
Glial Cells ◽  
Molecular Mechanisms ◽  
System Development ◽  
Fruit Fly ◽  
Nervous System Development ◽  
Wide Range ◽  
And Function

AbstractGlial cells play a wide range of essential roles in both nervous system development and function and has been reviewed recently (Parker and Auld, 2006). Glia provide an insulating sheath, either form or direct the formation of the blood–brain barrier, contribute to ion and metabolite homeostasis and provide guidance cues. Glial function often depends on the ability of glial cells to migrate toward specific locations during nervous system development. Work in nervous system development in insects, in particular in the fruit fly Drosophila melanogaster and the tobacco hornworm Manduca sexta, has provided significant insight into the roles of glia, although the molecular mechanisms underlying glial cell migration are being determined only now. Indeed, many of the processes and mechanisms discovered in these simpler systems have direct parallels in the development of vertebrate nervous systems. In this review, we first examine the developmental contexts in which invertebrate glial cell migration has been observed, we next discuss the characterized molecules required for proper glial cell migration, and we finally discuss future goals to be addressed in the study of glial cell development.

scholarly journals Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 660
Author(s):  
Mengdi Yu ◽  
Hongxia Zhang ◽  
Brian Wang ◽  
Yinuo Zhang ◽  
Xiaoying Zheng ◽  
...  
Keyword(s):  
Healthy Aging ◽  
Molecular Mechanisms ◽  
Mammalian Target Of Rapamycin ◽  
Adenosine Monophosphate ◽  
Sirtuin 1 ◽  
Public Health Issue ◽  
Biological Aging ◽  
Related Disease ◽  
Age Related ◽  
General Decline

Aging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.

scholarly journals The proteomic architecture of schizophrenia iPSC-derived cerebral organoids reveals alterations in GWAS and neuronal development factors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael Notaras ◽  
Aiman Lodhi ◽  
Haoyun Fang ◽  
David Greening ◽  
Dilek Colak
Keyword(s):  
High Throughput ◽  
Molecular Mechanisms ◽  
System Development ◽  
Early Adulthood ◽  
Enrichment Analysis ◽  
Nervous System Development ◽  
Model Systems ◽  
Proteomic Profiling ◽  
Human Brain Tissue ◽  
Brain Disorder

AbstractSchizophrenia (Scz) is a brain disorder that has a typical onset in early adulthood but otherwise maintains unknown disease origins. Unfortunately, little progress has been made in understanding the molecular mechanisms underlying neurodevelopment of Scz due to ethical and technical limitations in accessing developing human brain tissue. To overcome this challenge, we have previously utilized patient-derived Induced Pluripotent Stem Cells (iPSCs) to generate self-developing, self-maturating, and self-organizing 3D brain-like tissue known as cerebral organoids. As a continuation of this prior work, here we provide an architectural map of the developing Scz organoid proteome. Utilizing iPSCs from n = 25 human donors (n = 8 healthy Ctrl donors, and n = 17 Scz patients), we generated 3D cerebral organoids, employed 16-plex isobaric sample-barcoding chemistry, and simultaneously subjected samples to comprehensive high-throughput liquid-chromatography/mass-spectrometry (LC/MS) quantitative proteomics. Of 3,705 proteins identified by high-throughput proteomic profiling, we identified that just ~2.62% of the organoid global proteomic landscape was differentially regulated in Scz organoids. In sum, just 43 proteins were up-regulated and 54 were down-regulated in Scz patient-derived organoids. Notably, a range of neuronal factors were depleted in Scz organoids (e.g., MAP2, TUBB3, SV2A, GAP43, CRABP1, NCAM1 etc.). Based on global enrichment analysis, alterations in key pathways that regulate nervous system development (e.g., axonogenesis, axon development, axon guidance, morphogenesis pathways regulating neuronal differentiation, as well as substantia nigra development) were perturbed in Scz patient-derived organoids. We also identified prominent alterations in two novel GWAS factors, Pleiotrophin (PTN) and Podocalyxin (PODXL), in Scz organoids. In sum, this work serves as both a report and a resource that researchers can leverage to compare, contrast, or orthogonally validate Scz factors and pathways identified in observational clinical studies and other model systems.

scholarly journals Pairwise genetic meta-analyses between schizophrenia and substance dependence phenotypes reveals novel association signals

2021 ◽  
Author(s):  
Laura A. Greco ◽  
William R. Reay ◽  
Christopher V. Dayas ◽  
Murray J. Cairns
Keyword(s):  
Substance Use ◽  
Molecular Mechanisms ◽  
Substance Dependence ◽  
System Development ◽  
Causal Effect ◽  
Meta Analysis ◽  
Nervous System Development ◽  
Cannabis Use ◽  
Individual Substance ◽  
Meta Analyses

AbstractAlmost half of individuals diagnosed with schizophrenia also present with a substance use disorder, however, little is known about potential molecular mechanisms underlying this comorbidity. We used genetic analyses to enhance our understanding of the molecular overlap between these conditions. Our analyses revealed a positive genetic correlation between schizophrenia and the following dependence phenotypes: alcohol (rg = 0.3685, SE = 0.0768, P = 1.61 × 10−06), cannabis use disorder (rg = 0.309, SE = 0.0332, P = 1.19 × 10−20) and nicotine dependence (rg = 0.1177, SE = 0.0436, P = 7.0 × 10-03), as well as lifetime cannabis use (rg = 0.234, SE = 0.0298, P = 3.73 × 10−15) and drinks per week (rg = 0.0688, SE = 0.0217, P = 1.5 × 10−03). We further constructed latent causal variable (LCV) models to test for partial genetic causality and found evidence for a potential causal relationship between alcohol dependence and schizophrenia (GCP = 0.6, SE = 0.22, P = 1.6 × 10−03). This putative causal effect with schizophrenia was not seen using a continuous phenotype of drinks consumed per week, suggesting that distinct molecular mechanisms underlying dependence are involved in the relationship between alcohol and schizophrenia. To localise the specific genetic overlap between schizophrenia and substance use disorders, we conducted a gene-based and gene-set pairwise meta-analysis between schizophrenia and each of the four individual substance dependence phenotypes in up to 790,806 individuals. These bivariate meta-analyses identified 44 associations not observed in the individual GWAS, including five shared genes that play a key role in early central nervous system development. These genes may play an important role in substance dependence in schizophrenia, and, as a result, could represent important targets for future treatment or early intervention, as comorbid substance dependence is associated with poor treatment adherence, greater chronicity and increased mortality.

scholarly journals Biomarkers of Neurodegeneration and Precision Therapy in Retinal Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Alessandra Micera ◽  
Bijorn Omar Balzamino ◽  
Antonio Di Zazzo ◽  
Lucia Dinice ◽  
Stefano Bonini ◽  
...  
Keyword(s):  
Immune Cell ◽  
Current Knowledge ◽  
Age Related Macular Degeneration ◽  
Public Health Issue ◽  
Amyloid Formation ◽  
Retinal Diseases ◽  
Related Factors ◽  
Disease Evolution ◽  
Age Related ◽  
Tissue Aging

Vision-threatening retinal diseases affect millions of people worldwide, representing an important public health issue (high social cost) for both technologically advanced and new-industrialized countries. Overall RD group comprises the retinitis pigmentosa, the age-related macular degeneration (AMD), the diabetic retinopathy (DR), and idiopathic epiretinal membrane formation. Endocrine, metabolic, and even lifestyles risk factors have been reported for these age-linked conditions that represent a “public priority” also in this COVID-19 emergency. Chronic inflammation and neurodegeneration characterize the disease evolution, with a consistent vitreoretinal interface impairment. As the vitreous chamber is significantly involved, the latest diagnostic technologies of imaging (retina) and biomarker detection (vitreous) have provided a huge input at both medical and surgical levels. Complement activation and immune cell recruitment/infiltration as well as detrimental intra/extracellular deposits occur in association with a reactive gliosis. The cell/tissue aging route shows a specific signal path and biomolecular profile characterized by the increased expression of several glial-derived mediators, including angiogenic/angiostatic, neurogenic, and stress-related factors (oxidative stress metabolites, inflammation, and even amyloid formation). The possibility to access vitreous chamber by collecting vitreous reflux during intravitreal injection or obtaining vitreous biopsy during a vitrectomy represents a step forward for an individualized therapy. As drug response and protein signature appear unique in each single patient, therapies should be individualized. This review addresses the current knowledge about biomarkers and pharmacological targets in these vitreoretinal diseases. As vitreous fluids might reflect the early stages of retinal sufferance and/or late stages of neurodegeneration, the possibility to modulate intravitreal levels of growth factors, in combination to anti-VEGF therapy, would open to a personalized therapy of retinal diseases.

scholarly journals Strengthening Retina Eye Care Services in Nepal: Retina Eye Care of Nepal project

2020 ◽  
Author(s):  
Arjun Shrestha ◽  
Chunu Shrestha ◽  
Pratap Karki ◽  
Hara Maya Gurung ◽  
Takeshi Naito
Keyword(s):  
Low Income ◽  
Health Workers ◽  
Age Related Macular Degeneration ◽  
Low Income Countries ◽  
Public Health Issue ◽  
Hypertensive Retinopathy ◽  
Retinal Diseases ◽  
Eye Care ◽  
Care Services ◽  
Age Related

Abstract Recently causes of blindness are changing in Nepal. The number of people blind due to retinal diseases is increasing. Age-related macular degeneration (AMD), diabetic retinopathy (DR), hypertensive retinopathy, and retinal vein occlusion are the major retinal problems in Nepal. As the prevalence of vitreoretinal disorders is increasing with age, it indicates that retinal disorders will be a major public health issue with longevity in future[1].A rapid assessment of blindness conducted in 2010 had reported posterior segment problems as the second common cause of blindness, after cataract in Nepal[2]. Retinal diseases are very difficult to treat. Results from low-income countries show that many patients present only when they lose vision in both eyes. Delay in presentation was acknowledged as a significant problem and is often due to inadequate primary eye care and to misdiagnosis. Thus, it was highlighted that all ophthalmologists should be trained to recognize and manage retina problems. As blindness from DR is preventable, if caught and treated early, DR provides an excellent opportunity for secondary prevention strategies, such as screenings[3]. So, early diagnoses and preventions are very important. The projected population of Province 3 and 4 in Nepal is 60, 26,626, and 24, 72,494 respectively in the year 2016. There are altogether 6 tertiary retina care centers in Province 3 and 1 tertiary retina center in province 4 of Nepal to cover that much of the population. But, few eye doctors can treat patients with retinal diseases in Nepal. It is also necessary to train ophthalmic assistants, optometrists, ophthalmic nurses, and other health workers who can assist the treatment of retinal diseases. So, strengthening retina eye care services is very important in Nepal. Retina Eye Care of Nepal (RECON) project was a joint program of BP Eye Foundation, Kathmandu, Nepal, and Tokushima University, Japan to strengthen 3 retina centers in Province 1 and 1 retina center in province 4. The project duration was from May 2016 to February 2019. The purpose of RECON was to strengthen retina eye care services in Nepal by training ophthalmic human resources, enhancing retina eye care facilities, and conducting retina-screening camp.

scholarly journals The Proteomic Architecture of Schizophrenia Cerebral Organoids Reveals Alterations in GWAS and Neuronal Development Factors

2021 ◽  
Author(s):  
Michael Notaras ◽  
Aiman Lodhi ◽  
Haoyun Fang ◽  
David Greening ◽  
Dilek Colak
Keyword(s):  
High Throughput ◽  
Molecular Mechanisms ◽  
System Development ◽  
Early Adulthood ◽  
Enrichment Analysis ◽  
Nervous System Development ◽  
Model Systems ◽  
Proteomic Profiling ◽  
Human Brain Tissue ◽  
Brain Disorder

Schizophrenia (Scz) is a brain disorder that has a typical onset in early adulthood but otherwise maintains unknown disease origins. Unfortunately, little progress has been made in understanding the molecular mechanisms underlying neurodevelopment of Scz due to ethical and technical limitations in accessing developing human brain tissue. To overcome this challenge, we have previously utilized patient-derived Induced Pluripotent Stem Cells (iPSCs) to generate self-developing, self-maturating, and self-organizing 3D brain-like tissue known as cerebral organoids. As a continuation of this prior work [1], here we provide a molecular architectural map of the developing Scz organoid proteome. Utilizing iPSCs from n = 25 human donors (n = 8 healthy Ctrl donors, and n = 17 Scz patients), we generated 3D human cerebral organoids, employed 16-plex isobaric sample-barcoding chemistry, and simultaneously subjected samples to comprehensive high-throughput liquid-chromatography/mass-spectrometry (LC/MS) quantitative proteomics. Of 3,705 proteins identified by high-throughput proteomic profiling, we identified that just ~2.62% of the organoid global proteomic landscape was differentially regulated in Scz organoids. In sum, just 43 proteins were up-regulated and 54 were down-regulated in Scz patient-derived organoids. Notably, a range of neuronal factors were depleted in Scz organoids (e.g., MAP2, TUBB3, SV2A, GAP43, CRABP1, NCAM1 etc.). Based on global enrichment analysis, alterations in key pathways that regulate nervous system development (e.g., axonogenesis, axon development, axon guidance, morphogenesis pathways regulating neuronal differentiation, as well as substantia nigra development) were perturbed in Scz patient-derived organoids. We also identified prominent alterations in two novel GWAS factors, Pleiotrophin (PTN) and Podocalyxin (PODXL), in Scz organoids. In sum, this work serves as both a report and a resource whereby researchers can leverage human-derived neurodevelopmental data from Scz patients, which can be used to mine, compare, contrast, or orthogonally validate novel factors and pathways related to Scz risk identified in datasets from observational clinical studies and other model systems.

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