α-synuclein regulation of dopamine transporter

2012 ◽  
Vol 3 (3) ◽  
Author(s):  
Brittany Butler ◽  
Kaustuv Saha ◽  
Habibeh Khoshbouei
Keyword(s):  
Dopamine Transporter ◽  
Neurological Disorders ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Stable Complex ◽  
Early Event ◽  
Acid Protein ◽  
Neuronal Plasma Membrane ◽  
The Brain ◽  
Amino Acid Protein

AbstractThe development of effective therapeutic interventions for neurodegeneration requires a better understanding of the early events that precede neuronal loss. Recent work in various disease models has begun to emphasize the significance of presynaptic dysfunction as an early event that occurs before manifestation of neurological disorders. Dysregulation of dopamine (DA) homeostasis is implicated in neurodegenerative diseases, drug addiction, and neuropsychiatric disorders. The neuronal plasma membrane dopamine transporter (DAT) is essential for the maintenance of DA homeostasis in the brain. α-synuclein is a 140-amino acid protein that forms a stable complex with DAT and is linked to the pathogenesis of neurodegenerative disease. In this review we will examine the prevailing hypotheses for α-synuclein-regulation of DAT biology.

The aggregation and membrane-binding properties of an α-synuclein peptide fragment

2004 ◽  
Vol 32 (6) ◽  
pp. 1127-1129 ◽  
Author(s):  
J. Madine ◽  
A.J. Doig ◽  
D.A. Middleton
Keyword(s):  
Lipid Membranes ◽  
Synthetic Peptide ◽  
Membrane Binding ◽  
Phospholipid Bilayers ◽  
Peptide Fragment ◽  
Binding Properties ◽  
Hydrophobic Region ◽  
Acid Protein ◽  
The Brain ◽  
Amino Acid Protein

α-Synuclein is a 140 amino acid protein, which is associated with presynaptic membranes in the brain, and is the major component of protein aggregates produced during the progression of many neurodegenerative diseases. It has been shown that a central hydrophobic region of α-synuclein comprising residues 71–82 is required for aggregation of the protein into the fibrillar form found in pathogenic aggregates [Giasson, Murray, Trojanowski and Lee (2001) J. Biol. Chem. 276, 2380–2386]. In the present study, we used 2H NMR and electron microscopy to investigate the aggregation and membrane-binding properties of a synthetic peptide corresponding to this region. Results indicate that this region associates with phospholipid bilayers but also forms amyloid-like fibrils in the absence of lipid membranes.

scholarly journals The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress

2016 ◽  
Vol 2016 ◽  
pp. 1-13 ◽  
Author(s):  
Hugo Juárez Olguín ◽  
David Calderón Guzmán ◽  
Ernestina Hernández García ◽  
Gerardo Barragán Mejía
Keyword(s):  
Oxidative Stress ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Brain Dysfunction ◽  
Therapeutic Interventions ◽  
Antioxidant Compounds ◽  
Dopamine System ◽  
Health And Disease ◽  
The Brain

Dopamine is a neurotransmitter that is produced in the substantia nigra, ventral tegmental area, and hypothalamus of the brain. Dysfunction of the dopamine system has been implicated in different nervous system diseases. The level of dopamine transmission increases in response to any type of reward and by a large number of strongly additive drugs. The role of dopamine dysfunction as a consequence of oxidative stress is involved in health and disease. Introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the therapeutic potential of antioxidant compounds as a coadjuvant treatment to conventional neurological disorders is discussed.

scholarly journals Endocannabinoid Signaling for GABAergic-Microglia (Mis)Communication in the Brain Aging

2021 ◽  
Vol 14 ◽  
Author(s):  
Jorge Carrera ◽  
Jensen Tomberlin ◽  
John Kurtz ◽  
Eda Karakaya ◽  
Mehmet Bostanciklioglu ◽  
...  
Keyword(s):  
Communication System ◽  
Brain Aging ◽  
Neuronal Loss ◽  
Endocannabinoid System ◽  
Therapeutic Interventions ◽  
Aging Brain ◽  
Age Related ◽  
The Brain ◽  
Excessive Activation ◽  
By Products

The aging brain seems to be characterized by neuronal loss leading to cognitive decline and progressively worsening symptoms related to neurodegeneration. Also, pro-inflammatory states, if prolonged, may increase neuronal vulnerability via excessive activation of microglia and their pro-inflammatory by-products, which is seen as individuals increase in age. Consequently, microglial activity is tightly regulated by neuron-microglia communications. The endocannabinoid system (ECS) is emerging as a regulator of microglia and the neuronal-microglia communication system. Recently, it has been demonstrated that cannabinoid 1 (CB1) receptor signaling on GABAergic interneurons plays a crucial role in regulating microglial activity. Interestingly, if endocannabinoid signaling on GABAergic neurons are disturbed, the phenotypes mimic central nervous system insult models by activating microglia and leading to accelerated brain aging. Investigating the endocannabinoid receptors, ligands, and genetic deletions yields the potential to understand the communication system and mechanism by which the ECS regulates glial cells and aspects of aging. While there remains much to discover with the ECS, the information gathered and identified already could lead to the development of cell-specific therapeutic interventions that help in reducing the effects of age-related pro-inflammatory states and neurodegeneration.

Advances in Our Understanding of the Pathophysiology of Alzheimer’s Disease

US Neurology ◽  
2010 ◽  
Vol 06 (01) ◽  
pp. 28 ◽  
Author(s):  
Kim N Green ◽  
Steven S Schreiber ◽  
◽  
Keyword(s):  
Symptomatic Relief ◽  
Neuronal Loss ◽  
Current Understanding ◽  
Therapeutic Interventions ◽  
Disease Modification ◽  
The Past ◽  
Age Related ◽  
The Us ◽  
Alois Alzheimer ◽  
The Brain

Alzheimer’s disease (AD) is the most common age-related dementia, currently affecting more than 5 million patients in the US alone, and is characterized by the presence of both extracellular plaques and intraneuronal tangles in the brain of a patient with dementia. Alois Alzheimer first described the pathology associated with the disease over 100 years ago, and during the past three decades our understanding of the disease and of potential ways to treat it has increased tremendously. In this article we describe our current understanding of both the pathophysiology of Alzheimer’s disease and current and future therapeutic interventions, including symptomatic relief, disease modification, and the reversal of synaptic and neuronal loss.

scholarly journals Insights into Disease-Associated Tau Impact on Mitochondria

2020 ◽  
Vol 21 (17) ◽  
pp. 6344 ◽  
Author(s):  
Leonora Szabo ◽  
Anne Eckert ◽  
Amandine Grimm
Keyword(s):  
Cognitive Deficits ◽  
Tau Protein ◽  
Frontotemporal Lobar Degeneration ◽  
Therapeutic Interventions ◽  
Mitochondrial Proteins ◽  
Early Event ◽  
Substantial Evidence ◽  
Mitochondrial Functions ◽  
Underlying Mechanisms ◽  
The Brain

Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions.

Noninvasive disconnection of targeted neuronal circuitry sparing axons of passage and nonneuronal cells

2021 ◽  
pp. 1-11
Author(s):  
Yi Wang ◽  
Matthew J. Anzivino ◽  
Yanrong Zhang ◽  
Edward H. Bertram ◽  
James Woznak ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Focused Ultrasound ◽  
Focal Epilepsy ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Brain Parenchyma ◽  
The Brain ◽  
Patient Confidence ◽  
Treatment Envelope ◽  
Bbb Opening

OBJECTIVE Surgery can be highly effective for the treatment of medically intractable, neurological disorders, such as drug-resistant focal epilepsy. However, despite its benefits, surgery remains substantially underutilized due to both surgical concerns and nonsurgical impediments. In this work, the authors characterized a noninvasive, nonablative strategy to focally destroy neurons in the brain parenchyma with the goal of limiting collateral damage to nontarget structures, such as axons of passage. METHODS Low-intensity MR-guided focused ultrasound (MRgFUS), together with intravenous microbubbles, was used to open the blood-brain barrier (BBB) in a transient and focal manner in rats. The period of BBB opening was exploited to focally deliver to the brain parenchyma a systemically administered neurotoxin (quinolinic acid) that is well tolerated peripherally and otherwise impermeable to the BBB. RESULTS Focal neuronal loss was observed in targeted areas of BBB opening, including brain regions that are prime objectives for epilepsy surgery. Notably, other structures in the area of neuronal loss, including axons of passage, glial cells, vasculature, and the ventricular wall, were spared with this procedure. CONCLUSIONS These findings identify a noninvasive, nonablative approach capable of disconnecting neural circuitry while limiting the neuropathological consequences that attend other surgical procedures. Moreover, this strategy allows conformal targeting, which could enhance the precision and expand the treatment envelope for treating irregularly shaped surgical objectives located in difficult-to-reach sites. Finally, if this strategy translates to the clinic, the noninvasive nature and specificity of the procedure could positively influence both physician referrals for and patient confidence in surgery for medically intractable neurological disorders.

Nanoneuromedicines for Neurodegenerative Diseases

2018 ◽  
Vol 9 (1) ◽  
pp. 58-63
Author(s):  
Ram Singh ◽  
Geetanjali
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurodegenerative Diseases ◽  
Neurological Disorders ◽  
Clinical Symptoms ◽  
Neuronal Damage ◽  
Neuronal Loss ◽  
Sustained Delivery ◽  
Comprehensive Overview ◽  
The Brain ◽  
Lateral Sclerosis

Introduction: Neurodegenerative disease is a collective term for a number of diseases that affect the neurons in the human brain. The location of the neuronal loss in the brain leads to the specified disease based on the progression of the clinical symptoms. No drugs are available for complete cure of these diseases. Most of the drugs only slow down the progression of neuronal damage. The combination of drugs with nanotechnology gave a new promising hope for the treatment of neurological disorders. Nanomedicines are extremely useful for safe, effective, target oriented and sustained delivery. Due to their size in nanometer, they possess distinct and improved properties in comparison to their bulk counterpart. The utility of nanomedicines in neurological disorders including neurodegenerative diseases constitutes nanoneuromedicines. Conclusion: In this article, a comprehensive overview of the application of nanoneuromedicines in neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Amyotrophic Lateral Sclerosis (ALS) is provided.

Moving past the vaccine/autism controversy - to examine potential vaccine neurological harms

2020 ◽  
pp. 1-15
Author(s):  
Peter R. Breggin
Keyword(s):  
Neurological Disorders ◽  
Developmental Disorder ◽  
Physical Symptoms ◽  
Psychosocial Disorders ◽  
The Us ◽  
Potential Vaccine ◽  
Research And Education ◽  
The Brain ◽  
New Vaccines

BACKGROUND: The vaccine/autism controversy has caused vast scientific and public confusion, and it has set back research and education into genuine vaccine-induced neurological disorders. The great strawman of autism has been so emphasized by the vaccine industry that it, and it alone, often appears in authoritative discussions of adverse effects of the MMR and other vaccines. By dismissing the chimerical vaccine/autism controversy, vaccine defenders often dismiss all genuinely neurological aftereffects of the MMR (measles, mumps, and rubella) and other vaccines, including well-documented events, such as relatively rare cases of encephalopathy and encephalitis. OBJECTIVE: This report explains that autism is not a physical or neurological disorder. It is not caused by injury or disease of the brain. It is a developmental disorder that has no physical origins and no physical symptoms. It is extremely unlikely that vaccines are causing autism; but it is extremely likely that they are causing more neurological damage than currently appreciated, some of it resulting in psychosocial disabilities that can be confused with autism and other psychosocial disorders. This confusion between a developmental, psychosocial disorder and a physical neurological disease has played into the hands of interest groups who want to deny that vaccines have any neurological and associated neuropsychiatric effects. METHODS: A review of the scientific literature, textbooks, and related media commentary is integrated with basic clinical knowledge. RESULTS: This report shows how scientific sources have used the vaccine/autism controversy to avoid dealing with genuine neurological risks associated with vaccines and summarizes evidence that vaccines, including the MMR, can cause serious neurological disorders. Manufacturers have been allowed by the US Food and Drug Administration (FDA) to gain vaccine approval without placebo-controlled clinical trials. CONCLUSIONS: The misleading vaccine autism controversy must be set aside in favor of examining actual neurological harms associated with vaccines, including building on existing research that has been ignored. Manufacturers of vaccines must be required to conduct placebo-controlled clinical studies for existing vaccines and for government approval of new vaccines. Many probable or confirmed neurological adverse events occur within a few days or weeks after immunization and could be detected if the trials were sufficiently large. Contrary to current opinion, large, long-term placebo-controlled trials of existing and new vaccines would be relatively easy and safe to conduct.

scholarly journals Mechanisms of Neurodegeneration in Various Forms of Parkinsonism—Similarities and Differences

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 656
Author(s):  
Dariusz Koziorowski ◽  
Monika Figura ◽  
Łukasz M. Milanowski ◽  
Stanisław Szlufik ◽  
Piotr Alster ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Tau Protein ◽  
Protein Gene ◽  
Clinical Presentation ◽  
Neuronal Loss ◽  
Corticobasal Degeneration ◽  
Inflammatory Factors ◽  
Parkinsonian Disorders ◽  
Genetic Features ◽  
The Brain

Parkinson's disease (PD), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA) belong to a group of neurodegenerative diseases called parkinsonian syndromes. They share several clinical, neuropathological and genetic features. Neurodegenerative diseases are characterized by the progressive dysfunction of specific populations of neurons, determining clinical presentation. Neuronal loss is associated with extra- and intracellular accumulation of misfolded proteins. The parkinsonian diseases affect distinct areas of the brain. PD and MSA belong to a group of synucleinopathies that are characterized by the presence of fibrillary aggregates of α-synuclein protein in the cytoplasm of selected populations of neurons and glial cells. PSP is a tauopathy associated with the pathological aggregation of the microtubule associated tau protein. Although PD is common in the world's aging population and has been extensively studied, the exact mechanisms of the neurodegeneration are still not fully understood. Growing evidence indicates that parkinsonian disorders to some extent share a genetic background, with two key components identified so far: the microtubule associated tau protein gene (MAPT) and the α-synuclein gene (SNCA). The main pathways of parkinsonian neurodegeneration described in the literature are the protein and mitochondrial pathways. The factors that lead to neurodegeneration are primarily environmental toxins, inflammatory factors, oxidative stress and traumatic brain injury.

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