scholarly journals Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS

2017 ◽  
Vol 11 (3) ◽  
pp. 249-254 ◽  
Author(s):  
Álvaro C.B. Guedes ◽  
Ricardo Santin ◽  
André S.R. Costa ◽  
Keli C. Reiter ◽  
Arlete Hilbig ◽  
...  
Keyword(s):  
Entorhinal Cortex ◽  
Frontotemporal Lobar Degeneration ◽  
Scientific Literature ◽  
Cognitive Disorder ◽  
Brain Distribution ◽  
Abnormal Protein ◽  
Cellular Processes ◽  
The Central Nervous System ◽  
The Brain ◽  
Lateral Sclerosis

ABSTRACT INTRODUCTION: TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features. METHODS: We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD). After fixation and macroscopic examinations, sample analyses were performed. Specific regions were chosen for the application of immunohistochemistry (IHC) with anti-Aβ, AT8, anti-α-synuclein and anti-phospho-TDP-43. RESULTS: Both brains presented anti-phospho-TDP-43 positivity, but this was not equally distributed throughout the encephalic zones. In the FTD case, the studied brain presented phosphorylated TDP-43- in the frontal cortex, hippocampus, entorhinal cortex and mesencephalon; in the ALS-FTD case, the abnormal protein was also seen in the pons and medulla oblongata. The brain in the ALS-FTD case presented Aβ and AT8 positivity in the hippocampus and entorhinal cortex (Braak I and II). DISCUSSION: The hypothesis supported by scientific literature that these neurodegenerative diseases can have the same etiology with distinct encephalic region involvement is corroborated by the present study.

Neurotrophins and Proneurotrophins: Focus on Synaptic Activity and Plasticity in the Brain

2017 ◽  
Vol 23 (6) ◽  
pp. 587-604 ◽  
Author(s):  
Julien Gibon ◽  
Philip A. Barker
Keyword(s):  
Long Term Potentiation ◽  
Synaptic Activity ◽  
Cellular Processes ◽  
Term Potentiation ◽  
Neurotrophin 3 ◽  
New Findings ◽  
The Central Nervous System ◽  
The Brain

Neurotrophins have been intensively studied and have multiple roles in the brain. Neurotrophins are first synthetized as proneurotrophins and then cleaved intracellularly and extracellularly. Increasing evidences demonstrate that proneurotrophins and mature neurotrophins exerts opposing role in the central nervous system. In the present review, we explore the role of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) and their respective proform in cellular processes related to learning and memory. We focused on their roles in synaptic activity and plasticity in the brain with an emphasis on long-term potentiation, long-term depression, and basal synaptic transmission in the hippocampus and the temporal lobe area. We also discuss new findings on the role of the Val66Met polymorphism on the BDNF propeptide on synaptic activity.

scholarly journals Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases

2019 ◽  
Vol 20 (15) ◽  
pp. 3685 ◽  
Author(s):  
Roberta Cascella ◽  
Giulia Fani ◽  
Alessandra Bigi ◽  
Fabrizio Chiti ◽  
Cristina Cecchi
Keyword(s):  
Neurodegenerative Disorders ◽  
Frontotemporal Lobar Degeneration ◽  
Strong Influence ◽  
Genetic Mutations ◽  
Oxygen Species ◽  
Caspase Activation ◽  
Post Translational Modifications ◽  
Key Factor ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative disorders showing mislocalization and cytosolic accumulation of TDP-43 inclusions in the central nervous system. The decrease in the efficiency of the clearance systems in aging, as well as the presence of genetic mutations of proteins associated with cellular proteostasis in the familial forms of TDP-43 proteinopathies, suggest that a failure of these protein degradation systems is a key factor in the aetiology of TDP-43 associated disorders. Here we show that the internalization of human pre-formed TDP-43 aggregates in the murine neuroblastoma N2a cells promptly resulted in their ubiquitination and hyperphosphorylation by endogenous machineries, mimicking the post-translational modifications observed in patients. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. The inhibition of TDP-43 proteostasis in the presence of selective inhibitors against the proteasome and macroautophagy systems revealed that these two systems are both severely involved in TDP-43 accumulation and have a strong influence on each other in neurodegenerative disorders associated with TDP-43.

scholarly journals Can the Spinal Cord Learn and Remember?

2008 ◽  
Vol 8 ◽  
pp. 757-761 ◽  
Author(s):  
Pierre A. Guertin
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Nervous System ◽  
Cellular Mechanisms ◽  
Cellular Processes ◽  
Animal Data ◽  
The Central Nervous System ◽  
Review Reports ◽  
Specialized Region ◽  
The Brain

Learning and memory traditionally have been associated with cellular processes occurring in a specialized region of the brain called the hippocampus. However, recent data have provided strong evidence to suggest that comparable processes are also expressed in the spinal cord. Experiments performed mainly in spinal cord–transected animals have reported that, indeed, spinal-mediated functions, such as the stretch or flexion reflex, pain signaling, micturition, or locomotion, may undergo plasticity changes associated with partial functional recovery that occur spontaneously or conditionally. Many of the underlying cellular mechanisms strikingly resemble those found in the hippocampus. This mini-review reports, mainly, animal data that support the idea that other areas of the central nervous system, such as the spinal cord, can also learn and remember.

scholarly journals Emerging Roles of Extracellular Vesicles in the Central Nervous System: Physiology, Pathology, and Therapeutic Perspectives

2021 ◽  
Vol 15 ◽  
Author(s):  
Yadaly Gassama ◽  
Alexandre Favereaux
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Extracellular Vesicles ◽  
Cell Types ◽  
Cellular Processes ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
System Physiology ◽  
The Brain

Extracellular vesicles or EVs are secreted by most, if not all, eukaryote cell types and recaptured by neighboring or distant cells. Their cargo, composed of a vast diversity of proteins, lipids, and nucleic acids, supports the EVs’ inter-cellular communication. The role of EVs in many cellular processes is now well documented both in physiological and pathological conditions. In this review, we focus on the role of EVs in the central nervous system (CNS) in physiological as well as pathological conditions such as neurodegenerative diseases or brain cancers. We also discuss the future of EVs in clinical research, in particular, their value as biomarkers as well as innovative therapeutic agents. While an increasing number of studies reveal EV research as a promising field, progress in the standardization of protocols and innovation in analysis as well as in research tools is needed to make a breakthrough in our understanding of their impact in the pathophysiology of the brain.

scholarly journals Adult onset pan-neuronal human tau tubulin kinase 1 expression causes severe cerebellar neurodegeneration in mice

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Pamela McMillan ◽  
Jeanna Wheeler ◽  
Rachel E. Gatlin ◽  
Laura Taylor ◽  
Tim Strovas ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia ◽  
Memory Impairment ◽  
Spinocerebellar Ataxia Type ◽  
Adult Onset ◽  
Protein Deposition ◽  
Protein Levels ◽  
The Central Nervous System ◽  
Progressive Weight Loss ◽  
The Brain ◽  
Lateral Sclerosis

AbstractThe kinase TTBK1 is predominantly expressed in the central nervous system and has been implicated in neurodegenerative diseases including Alzheimer’s disease, frontotemporal lobar degeneration, and amyotrophic lateral sclerosis through its ability to phosphorylate the proteins tau and TDP-43. Mutations in the closely related gene TTBK2 cause spinocerebellar ataxia, type 11. However, it remains unknown whether altered TTBK1 activity alone can drive neurodegeneration. In order to characterize the consequences of neuronal TTBK1 upregulation in adult brains, we have generated a transgenic mouse model with inducible pan-neuronal expression of human TTBK1. We find that these inducible TTBK1 transgenic mice (iTTBK1 Tg) exhibit motor and cognitive phenotypes, including decreased grip strength, hyperactivity, limb-clasping, and spatial memory impairment. These behavioral phenotypes occur in conjunction with progressive weight loss, neuroinflammation, and severe cerebellar degeneration with Purkinje neuron loss. Phenotype onset begins weeks after TTBK1 induction, culminating in average mortality around 7 weeks post induction. The iTTBK1 Tg animals lack any obvious accumulation of pathological tau or TDP-43, indicating that TTBK1 expression drives neurodegeneration in the absence of detectable pathological protein deposition. In exploring TTBK1 functions, we identified the autophagy related protein GABARAP to be a novel interacting partner of TTBK1 and show that GABARAP protein levels increase in the brain following induction of TTBK1. These iTTBK1 Tg mice exhibit phenotypes reminiscent of spinocerebellar ataxia, and represent a new model of cerebellar neurodegeneration.

Role of zinc and copper ions in the pathogenetic mechanisms of traumatic brain injury and Alzheimer’s disease

2020 ◽  
Vol 31 (3) ◽  
pp. 233-243 ◽  
Author(s):  
Nickolay K. Isaev ◽  
Elena V. Stelmashook ◽  
Elisaveta E. Genrikhs
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Copper Ions ◽  
Research Data ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Β Amyloid ◽  
The Brain ◽  
Lateral Sclerosis

AbstractThe disruption of homeostasis of zinc (Zn2+) and copper (Cu2+) ions in the central nervous system is involved in the pathogenesis of many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Wilson’s, Creutzfeldt-Jakob, Parkinson’s, and Alzheimer’s diseases (AD), and traumatic brain injury (TBI). The last two pathological conditions of the brain are the most common; moreover, it is possible that TBI is a risk factor for the development of AD. Disruptions of Zn2+ and Cu2+ homeostasis play an important role in the mechanisms of pathogenesis of both TBI and AD. This review attempts to summarize and systematize the currently available research data on this issue. The neurocytotoxicity of Cu2+ and Zn2+, the synergism of the toxic effect of calcium and Zn2+ ions on the mitochondria of neurons, and the interaction of Zn2+ and Cu2+ with β-amyloid (Abeta) and tau protein are considered.

scholarly journals Is Modulation of Oxidative Stress an Answer? The State of the Art of Redox Therapeutic Actions in Neurodegenerative Diseases

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Valerio Chiurchiù ◽  
Antonio Orlacchio ◽  
Mauro Maccarrone
Keyword(s):  
Oxidative Stress ◽  
Neurodegenerative Diseases ◽  
Therapeutic Strategy ◽  
Neuronal Loss ◽  
Spastic Paraplegia ◽  
The Central Nervous System ◽  
High Production ◽  
The Brain ◽  
Lateral Sclerosis

The central nervous system is particularly sensitive to oxidative stress due to many reasons, including its high oxygen consumption even under basal conditions, high production of reactive oxygen and nitrogen species from specific neurochemical reactions, and the increased deposition of metal ions in the brain with aging. For this reason, along with inflammation, oxidative stress seems to be one of the main inducers of neurodegeneration, causing excitotoxicity, neuronal loss, and axonal damage, ultimately being now considered a key element in the onset and progression of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, multiple sclerosis, and hereditary spastic paraplegia. Thus, the present paper reviews the role of oxidative stress and of its mechanistic insights underlying the pathogenesis of these neurodegenerative diseases, with particular focus on current studies on its modulation as a potential and promising therapeutic strategy.

scholarly journals Copper, Iron, and Manganese Toxicity in Neuropsychiatric Conditions

2021 ◽  
Vol 22 (15) ◽  
pp. 7820
Author(s):  
Beata Tarnacka ◽  
Anna Jopowicz ◽  
Maria Maślińska
Keyword(s):  
Good Health ◽  
Hyperactivity Disorder ◽  
Copper Manganese ◽  
The Central Nervous System ◽  
Enzyme Superoxide Dismutase ◽  
And Function ◽  
The Brain ◽  
Neuropsychiatric Conditions ◽  
Lateral Sclerosis ◽  
Iron And Manganese

Copper, manganese, and iron are vital elements required for the appropriate development and the general preservation of good health. Additionally, these essential metals play key roles in ensuring proper brain development and function. They also play vital roles in the central nervous system as significant cofactors for several enzymes, including the antioxidant enzyme superoxide dismutase (SOD) and other enzymes that take part in the creation and breakdown of neurotransmitters in the brain. An imbalance in the levels of these metals weakens the structural, regulatory, and catalytic roles of different enzymes, proteins, receptors, and transporters and is known to provoke the development of various neurological conditions through different mechanisms, such as via induction of oxidative stress, increased α-synuclein aggregation and fibril formation, and stimulation of microglial cells, thus resulting in inflammation and reduced production of metalloproteins. In the present review, the authors focus on neurological disorders with psychiatric signs associated with copper, iron, and manganese excess and the diagnosis and potential treatment of such disorders. In our review, we described diseases related to these metals, such as aceruloplasminaemia, neuroferritinopathy, pantothenate kinase-associated neurodegeneration (PKAN) and other very rare classical NBIA forms, manganism, attention-deficit/hyperactivity disorder (ADHD), ephedrone encephalopathy, HMNDYT1-SLC30A10 deficiency (HMNDYT1), HMNDYT2-SLC39A14 deficiency, CDG2N-SLC39A8 deficiency, hepatic encephalopathy, prion disease and “prion-like disease”, amyotrophic lateral sclerosis, Huntington’s disease, Friedreich’s ataxia, and depression.

scholarly journals TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers

2021 ◽  
Author(s):  
Behzad Khoshnood ◽  
Abbe Ullgren ◽  
Jose Laffita-Mesa ◽  
Linn Öijerstedt ◽  
Kalicharan Patra ◽  
...  
Keyword(s):  
Neurodegenerative Disease ◽  
Frontotemporal Lobar Degeneration ◽  
Splice Mutation ◽  
Post Mortem ◽  
Mutation Carriers ◽  
Swedish Family ◽  
Post Mortem Brain ◽  
History Of ◽  
The Brain ◽  
Lateral Sclerosis

Abstract Background Frontotemporal dementia (FTD) is a neurodegenerative disease, resulting in progressive problems in language and/or behaviour and is often diagnosed before 65 years of age. Ubiquitin positive protein aggregates in the brain are among the key pathologic hallmarks of frontotemporal lobar degeneration (FTLD) postmortem. The TANK-binding kinase 1 gene (TBK1) is on the list of genes that can contribute to the development of FTD as well as the related neurodegenerative disease amyotrophic lateral sclerosis (ALS). Methods In this study, using an array of clinical and neuropathological data combined with biochemical and proteomics assays, we analyze the TBK1 splice-mutation (c.1340 + 1G > A) in a Swedish family with a history of FTD and ALS. We also explore the K63 ubiquitination landscape in post-mortem brain tissue and fibroblast cultures. Results The intronic (c.1340 + 1G > A) mutation in TBK1 results in haploinsufficiency and affects the activity of the protein in symptomatic and pre-symptomatic mutation carriers. Conclusion Our results suggest that the mutation leads to a significant reduction of TBK1 activity and induce alterations in K63 ubiquitination profile of the cell already in the presymptomatic stages.

Presence of antibody in virus-infected brain cells of SSPE ferrets

1983 ◽  
Vol 41 ◽  
pp. 804-805
Author(s):  
Hannah R. Brown ◽  
Tammy L. Donato ◽  
Halldor Thormar
Keyword(s):  
Measles Virus ◽  
Plasma Cells ◽  
Subacute Sclerosing Panencephalitis ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Brain Cells ◽  
Antibody Titers ◽  
A Cell ◽  
The Central Nervous System ◽  
The Brain

Measles virus specific immunoglobulin G (IgG) has been found in the brains of patients with subacute sclerosing panencephalitis (SSPE), a slowly progressing disease of the central nervous system (CNS) in children. IgG/albumin ratios indicate that the antibodies are synthesized within the CNS. Using the ferret as an animal model to study the disease, we have been attempting to localize the Ig's in the brains of animals inoculated with a cell associated strain of SSPE. In an earlier report, preliminary results using Protein A conjugated to horseradish peroxidase (PrAPx) (Dynatech Diagnostics Inc., South Windham, ME.) to detect antibodies revealed the presence of immunoglobulin mainly in antibody-producing plasma cells in inflammatory lesions and not in infected brain cells.In the present experiment we studied the brain of an SSPE ferret with neutralizing antibody titers of 1:1024 in serum and 1:512 in CSF at time of sacrifice 7 months after i.c. inoculation with SSPE measles virus-infected cells. The animal was perfused with saline and portions of the brain and spinal cord were immersed in periodate-lysine-paraformaldehyde (P-L-P) fixative. The ferret was not perfused with fixative because parts of the brain were used for virus isolation.

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