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Stem Cell Research & Therapy Dec 2021Optic neuritis (ON) is frequently encountered in multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein associated disease,... (Review)
Review
BACKGROUND
Optic neuritis (ON) is frequently encountered in multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein associated disease, and other systemic autoimmune disorders. The hallmarks are an abnormal optic nerve and inflammatory demyelination; episodes of optic neuritis tend to be recurrent, and particularly for neuromyelitis optica spectrum disorder, may result in permanent vision loss.
MAIN BODY
Mesenchymal stem cell (MSC) therapy is a promising approach that results in remyelination, neuroprotection of axons, and has demonstrated success in clinical studies in other neuro-degenerative diseases and in animal models of ON. However, cell transplantation has significant disadvantages and complications. Cell-free approaches utilizing extracellular vesicles (EVs) produced by MSCs exhibit anti-inflammatory and neuroprotective effects in multiple animal models of neuro-degenerative diseases and in rodent models of multiple sclerosis (MS). EVs have potential to be an effective cell-free therapy in optic neuritis because of their anti-inflammatory and remyelination stimulating properties, ability to cross the blood brain barrier, and ability to be safely administered without immunosuppression.
CONCLUSION
We review the potential application of MSC EVs as an emerging treatment strategy for optic neuritis by reviewing studies in multiple sclerosis and related disorders, and in neurodegeneration, and discuss the challenges and potential rewards of clinical translation of EVs including cell targeting, carrying of therapeutic microRNAs, and prolonging delivery for treatment of optic neuritis.
Topics: Animals; Extracellular Vesicles; Mesenchymal Stem Cells; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica; Optic Neuritis
PubMed: 34863294
DOI: 10.1186/s13287-021-02645-7 -
Molecular Psychiatry Jan 2023Growing evidence suggests that Rho GTPases and molecules involved in their signaling pathways play a major role in the development of the central nervous system (CNS).... (Review)
Review
Growing evidence suggests that Rho GTPases and molecules involved in their signaling pathways play a major role in the development of the central nervous system (CNS). Whole exome sequencing (WES) and de novo examination of mutations, including SNP (Single Nucleotide Polymorphism) in genes coding for the molecules of their signaling cascade, has allowed the recent discovery of dominant autosomic mutations and duplication or deletion of candidates in the field of neurodevelopmental diseases (NDD). Epidemiological studies show that the co-occurrence of several of these neurological pathologies may indeed be the rule. The regulators of Rho GTPases have often been considered for cognitive diseases such as intellectual disability (ID) and autism. But, in a remarkable way, mild to severe motor symptoms are now reported in autism and other cognitive NDD. Although a more abundant litterature reports the involvement of Rho GTPases and signaling partners in cognitive development, molecular investigations on their roles in central nervous system (CNS) development or degenerative CNS pathologies also reveal their role in embryonic and perinatal motor wiring through axon guidance and later in synaptic plasticity. Thus, Rho family small GTPases have been revealed to play a key role in brain functions including learning and memory but their precise role in motor development and associated symptoms in NDD has been poorly scoped so far, despite increasing clinical data highlighting the links between cognition and motor development. Indeed, early impairements in fine or gross motor performance is often an associated feature of NDDs, which then impact social communication, cognition, emotion, and behavior. We review here recent insights derived from clinical developmental neurobiology in the field of Rho GTPases and NDD (autism spectrum related disorder (ASD), ID, schizophrenia, hypotonia, spastic paraplegia, bipolar disorder and dyslexia), with a specific focus on genetic alterations affecting Rho GTPases that are involved in motor circuit development.
Topics: Humans; Motor Disorders; rho GTP-Binding Proteins; Neurodevelopmental Disorders; Intellectual Disability; Autistic Disorder
PubMed: 35918397
DOI: 10.1038/s41380-022-01702-8 -
Survey of Ophthalmology 2023Fovea centralis, located at the center of the macula, is packed with cone photoreceptors and is responsible for central visual acuity. Isolated foveal photoreceptor... (Review)
Review
Fovea centralis, located at the center of the macula, is packed with cone photoreceptors and is responsible for central visual acuity. Isolated foveal photoreceptor disruption may occur in a variety of hereditary, degenerative, traumatic, and toxic chorioretinal diseases. These have been known previously by multiple synonyms including macular microhole, foveal spot, and outer foveal microdefects. A common clinical feature underlying these conditions is the presence of apparently normal fovea or subtle hypopigmented lesion at the foveal or juxtafoveal area. A detailed history along with high-resolution optical coherence tomography is often helpful to derive a conclusive diagnosis in majority of these cases. Focal photoreceptor disruption usually involves loss or rarefaction of ellipsoid/interdigitation zone, either in isolation or associated with external limiting membrane or retinal pigment epithelium disruption in the fovea. Vitreomacular interface (VMI) disorders including vitreomacular traction, posterior vitreous detachment, epiretinal membrane, and impending macular hole possibly remain the most common cause. Retinal dystrophies such as cone dystrophy, occult macular dystrophy, and achromatopsia may present with diminution of vision and normal appearing fundus in a younger age group. Other causes include photic retinopathy (e.g., from a history of sun gazing or laser pointer exposure), blunt trauma, drug exposure (e.g., poppers maculopathy or tamoxifen retinopathy), and acute retinal pigment epitheliopathy (ARPE). Visual prognosis depends on the underlying etiology with complete recovery common in the subset of patients with VMI, and ARPE, whereas persistent outer retinal defects are the rule in other conditions. We discuss the differential diagnoses that lead to isolated foveal photoreceptor defects. Identifying and understanding the underlying disease processes that cause foveal photoreceptor disruption may help predict visual prognosis.
Topics: Humans; Fovea Centralis; Tomography, Optical Coherence; Diagnosis, Differential; Retinal Diseases; Retinal Perforations; Eye Diseases; Retrospective Studies
PubMed: 36934831
DOI: 10.1016/j.survophthal.2023.03.003 -
Experimental Biology and Medicine... Oct 2020Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally... (Review)
Review
Brain degenerative disorders, which include some neurodevelopmental disorders and age-associated diseases, cause debilitating neurological deficits and are generally fatal. A large body of emerging evidence indicates that iron accumulation in neurons within specific regions of the brain plays an important role in the pathogenesis of many of these disorders. Iron homeostasis is a highly complex and incompletely understood process involving a large number of regulatory molecules. Our review provides a description of what is known about how iron is obtained by the body and brain and how defects in the homeostatic processes could contribute to the development of brain diseases, focusing on Alzheimer's disease and Parkinson's disease as well as four other disorders belonging to a class of inherited conditions referred to as neurodegeneration based on iron accumulation (NBIA) disorders. A description of potential therapeutic approaches being tested for each of these different disorders is provided.
Topics: Animals; Biological Transport; Brain; Homeostasis; Humans; Iron; Models, Biological; Neurodegenerative Diseases
PubMed: 32878460
DOI: 10.1177/1535370220953065 -
Aging and Disease Apr 2020Aging is an inevitable time-dependent decline of various physiological functions that finally leads to death. Progressive protein damage and aggregation have been... (Review)
Review
Aging is an inevitable time-dependent decline of various physiological functions that finally leads to death. Progressive protein damage and aggregation have been proposed as the root cause of imbalance in regulatory processes and risk factors for aging and neurodegenerative diseases. Oxygen is a modulator of aging. The oxygen-deprived conditions (hypoxia) leads to oxidative stress, cellular damage and protein modifications. Despite unambiguous evidence of the critical role of spontaneous non-enzymatic Degenerative Protein Modifications (DPMs) such as oxidation, glycation, carbonylation, carbamylation, and deamidation, that impart deleterious structural and functional protein alterations during aging and age-associated disorders, the mechanism that mediates these modifications is poorly understood. This review summarizes up-to-date information and recent developments that correlate DPMs, aging, hypoxia, and age-associated neurodegenerative diseases. Despite numerous advances in the study of the molecular hallmark of aging, hypoxia, and degenerative protein modifications during aging and age-associated pathologies, a major challenge remains there to dissect the relative contribution of different DPMs in aging (either natural or hypoxia-induced) and age-associated neurodegeneration.
PubMed: 32257546
DOI: 10.14336/AD.2019.0604 -
Sleep Medicine Reviews Apr 2023Sleep disorders (SDs) are common non-motor symptoms of Parkinson's disease (PD) with wide variability in their prevalence rates. The etiology of SDs in PD is... (Meta-Analysis)
Meta-Analysis Review
Sleep and wakefulness disturbances in Parkinson's disease: A meta-analysis on prevalence and clinical aspects of REM sleep behavior disorder, excessive daytime sleepiness and insomnia.
Sleep disorders (SDs) are common non-motor symptoms of Parkinson's disease (PD) with wide variability in their prevalence rates. The etiology of SDs in PD is multifactorial because the degenerative processes underlying the disease and their interaction with drugs and clinical features may promote REM sleep behavior disorder (RBD), excessive daytime sleepiness (EDS) and insomnia. Therefore, we designed a meta-analytic study to provide a reliable estimate of the prevalence and associated clinical and neuropsychiatric aspects of SDs in PD. A systematic literature search was performed up to February 2022. Pooled RBD prevalence was 46%, and its occurrence was associated with older age, lower education, longer disease duration, higher levodopa equivalent daily dose (LEDD), worse motor and autonomic manifestations, poorer quality of life and autonomy, and more severe neuropsychiatric symptoms. The pooled prevalence of EDS was 35% and was associated with older age, longer disease duration, worse motor and autonomic symptoms, higher LEDD, reduced autonomy, and more severe neuropsychiatric symptoms. Insomnia was reported in 44% of PD patients and was related to longer disease duration, higher LEDD, and more severe depression. SDs are associated with a more severe PD clinical phenotype; further studies should explore the pathophysiological mechanisms underlying SDs and develop targeted therapeutic strategies.
Topics: Humans; REM Sleep Behavior Disorder; Parkinson Disease; Wakefulness; Sleep Initiation and Maintenance Disorders; Quality of Life; Prevalence; Sleep; Disorders of Excessive Somnolence; Sleep Wake Disorders
PubMed: 36708642
DOI: 10.1016/j.smrv.2023.101759 -
The Canadian Journal of Neurological... Mar 2023The complement system is a tightly controlled signaling network that plays a role in innate immune surveillance. However, abnormal signaling through this pathway... (Review)
Review
The complement system is a tightly controlled signaling network that plays a role in innate immune surveillance. However, abnormal signaling through this pathway contributes to tissue damage in several inflammatory, autoimmune, and degenerative diseases. Myasthenia gravis (MG) and neuromyelitis optica spectrum disorders (NMOSD) have complement dysfunction at the core of pathogenesis, providing a strong rationale for therapeutic targeting of complement components. The purpose of this paper is to briefly review the role of complement activation in the pathogenesis of MG and NMOSD, to discuss the rationale and evidence for complement inhibition as a method to manage these diseases, and to provide a Canadian perspective on the use of complement inhibition therapy through real-world cases of MG and NMOSD.
Topics: Humans; Neuromyelitis Optica; Canada; Myasthenia Gravis; Immunologic Factors
PubMed: 34895385
DOI: 10.1017/cjn.2021.508 -
Frontiers in Molecular Neuroscience 2020The most evident phenotype of degenerative motoneuron disease is the loss of motor function which accompanies motoneuron death. In both amyotrophic lateral sclerosis... (Review)
Review
The most evident phenotype of degenerative motoneuron disease is the loss of motor function which accompanies motoneuron death. In both amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA), it is now clear that dysfunction is not restricted to motoneurons but is manifest in the spinal circuits in which motoneurons are embedded. As mounting evidence shows that motoneurons possess more elaborate and extensive connections within the spinal cord than previously realized, it is necessary to consider the role of this circuitry and its dysfunction in the disease process. In this review article, we ask if the selective vulnerability of the different motoneuron types and the relative disease resistance of distinct motoneuron groups can be understood in terms of their intraspinal connections.
PubMed: 32523513
DOI: 10.3389/fnmol.2020.00074 -
Cells Jan 2021The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven... (Review)
Review
The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and in aging-driven degenerative diseases. mPTP activity accelerates aging by releasing large amounts of cell-damaging reactive oxygen species, Ca and NAD. The various pathways that control the channel activity, directly or indirectly, can therefore either inhibit or accelerate aging or retard or enhance the progression of aging-driven degenerative diseases and determine lifespan and healthspan. Autophagy, a catabolic process that removes and digests damaged proteins and organelles, protects the cell against aging and disease. However, the protective effect of autophagy depends on mTORC2/SKG1 inhibition of mPTP. Autophagy is inhibited in aging cells. Mitophagy, a specialized form of autophagy, which retards aging by removing mitochondrial fragments with activated mPTP, is also inhibited in aging cells, and this inhibition leads to increased mPTP activation, which is a major contributor to neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. The increased activity of mPTP in aging turns autophagy/mitophagy into a destructive process leading to cell aging and death. Several drugs and lifestyle modifications that enhance healthspan and lifespan enhance autophagy and inhibit the activation of mPTP. Therefore, elucidating the intricate connections between pathways that activate and inhibit mPTP, in the context of aging and degenerative diseases, could enhance the discovery of new drugs and lifestyle modifications that slow aging and degenerative disease.
Topics: Animals; Autophagy; Disease; Humans; Longevity; Mitochondrial Permeability Transition Pore; Mitophagy; Models, Biological
PubMed: 33418876
DOI: 10.3390/cells10010079 -
Current Medicinal Chemistry 2021The present review aims to provide a complete and comprehensive summary of current literature relevant to oxysterols and related diseases. Oxidation of cholesterol leads... (Review)
Review
The present review aims to provide a complete and comprehensive summary of current literature relevant to oxysterols and related diseases. Oxidation of cholesterol leads to the formation of a large number of oxidized products, generally known as oxysterols. They are intermediates in the biosynthesis of bile acids, steroid hormones, and 1,25- dihydroxyvitamin D3. Although oxysterols are considered as metabolic intermediates, there is a growing body of evidence that many of them are bioactive, and their absence or excess may be part of the cause of a disease phenotype. These compounds derive from either enzymatic or non-enzymatic oxidation of cholesterol. This study provides comprehensive information about the structures, formation, and types of oxysterols even when involved in certain disease states, focusing on their effects on metabolism and linkages with these diseases. The role of specific oxysterols as mediators in various disorders, such as degenerative (age-related) and cancer-related disorders, has now become clearer. Oxysterol levels may be employed as suitable markers for the diagnosis of specific diseases or in predicting the incidence rate of diseases, such as diabetes mellitus, Alzheimer's disease, multiple sclerosis, osteoporosis, lung cancer, breast cancer, and infertility. However, further investigations may be required to confirm these mentioned possibilities.
Topics: Cholesterol; Disease; Humans; Oxidation-Reduction; Oxysterols
PubMed: 32175830
DOI: 10.2174/0929867327666200316142659