scholarly journals Psychomotor impairments and therapeutic implications revealed by a mutation associated with infantile Parkinsonism-Dystonia

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jenny I Aguilar ◽  
Mary Hongying Cheng ◽  
Josep Font ◽  
Alexandra C Schwartz ◽  
Kaitlyn Ledwitch ◽  
...  
Keyword(s):  
High Speed ◽  
Molecular Mechanisms ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Expression System ◽  
Distinct Type ◽  
Underlying Disease ◽  
Deficiency Syndrome ◽  
Motor Deficits ◽  
Therapeutic Implications

Parkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution. We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination with chloroquine, a lysosomal inhibitor that enhanced DAT expression in a heterologous expression system. Together, these studies shed some light on how a DTDS-linked DAT mutation underlies DA dysfunction and, possibly, clinical phenotypes shared by DTDS and PD.

scholarly journals Psychomotor Impairments and Therapeutic Implications Revealed by a Mutation Associated with Infantile Parkinsonism-Dystonia

2021 ◽  
Author(s):  
Jenny I. Aguilar ◽  
Mary Hongying Cheng ◽  
Josep Font ◽  
Alexandra C. Schwartz ◽  
Kaitlyn Ledwitch ◽  
...  
Keyword(s):  
High Speed ◽  
Molecular Mechanisms ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Distinct Type ◽  
Surface Expression ◽  
Underlying Disease ◽  
Deficiency Syndrome ◽  
Motor Deficits ◽  
Therapeutic Implications

ABSTRACTParkinson disease (PD) is a progressive, neurodegenerative disorder affecting over 6.1 million people worldwide. Although the cause of PD remains unclear, studies of highly-penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the molecular mechanisms underlying disease pathology. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a distinct type of infantile parkinsonism-dystonia that shares key clinical features with PD, including motor deficits (progressive bradykinesia, tremor, hypomimia) and altered DA neurotransmission. Here, we define structural, functional, and behavioral consequences of a Cys substitution at R445 in human DAT (hDAT R445C), identified in a patient with DTDS. We found that this R445 substitution disrupts a phylogenetically conserved intracellular (IC) network of interactions that compromise the hDAT IC gate. This is demonstrated by both Rosetta molecular modeling and fine-grained simulations using hDAT R445C, as well as EPR analysis and X-ray crystallography of the bacterial homolog leucine transporter. Notably, the disruption of this IC network of interactions supported a channel-like intermediate of hDAT and compromised hDAT function. We demonstrate that Drosophila melanogaster expressing hDAT R445C show impaired hDAT activity, which is associated with DA dysfunction in isolated brains and with abnormal behaviors monitored at high-speed time resolution.We show that hDAT R445C Drosophila exhibit motor deficits, lack of motor coordination (i.e. flight coordination) and phenotypic heterogeneity in these behaviors that is typically associated with DTDS and PD. These behaviors are linked with altered dopaminergic signaling stemming from loss of DA neurons and decreased DA availability. We rescued flight coordination through enhanced DAT surface expression via the lysosomal inhibitor chloroquine. Together, these studies shed light on how a DTDS-linked DAT mutation underlies DA dysfunction and, more broadly, the clinical phenotypes shared by DTDS and PD.

scholarly journals Amyloidosis in Alzheimer’s Disease: The Toxicity of Amyloid Beta (Aβ), Mechanisms of Its Accumulation and Implications of Medicinal Plants for Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Anchalee Prasansuklab ◽  
Tewin Tencomnao
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Herbal Medicines ◽  
Underlying Disease ◽  
Current Therapy ◽  
The Central Nervous System ◽  
Number Of Individuals

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to memory deficits and death. While the number of individuals with AD is rising each year due to the longer life expectancy worldwide, current therapy can only somewhat relieve the symptoms of AD. There is no proven medication to cure or prevent the disease, possibly due to a lack of knowledge regarding the molecular mechanisms underlying disease pathogenesis. Most previous studies have accepted the “amyloid hypothesis,” in which the neuropathogenesis of AD is believed to be triggered by the accumulation of the toxic amyloid beta (Aβ) protein in the central nervous system (CNS). Lately, knowledge that may be critical to unraveling the hidden pathogenic pathway of AD has been revealed. This review concentrates on the toxicity of Aβand the mechanism of accumulation of this toxic protein in the brain of individuals with AD and also summarizes recent advances in the study of these accumulation mechanisms together with the role of herbal medicines that could facilitate the development of more effective therapeutic and preventive strategies.

scholarly journals Adhesion ofPlasmodium falciparum-infected erythrocytes to human cells: molecular mechanisms and therapeutic implications

2009 ◽  
Vol 11 ◽  
Author(s):  
J. Alexandra Rowe ◽  
Antoine Claessens ◽  
Ruth A. Corrigan ◽  
Mònica Arman
Keyword(s):  
Mortality Rate ◽  
Severe Malaria ◽  
High Mortality ◽  
Molecular Mechanisms ◽  
Disease Process ◽  
Underlying Disease ◽  
Human Cells ◽  
Sub Saharan Africa ◽  
Therapeutic Implications ◽  
Sub Saharan

Severe malaria has a high mortality rate (15–20%) despite treatment with effective antimalarial drugs. Adjunctive therapies for severe malaria that target the underlying disease process are therefore urgently required. Adhesion of erythrocytes infected withPlasmodium falciparumto human cells has a key role in the pathogenesis of life-threatening malaria and could be targeted with antiadhesion therapy. Parasite adhesion interactions include binding to endothelial cells (cytoadherence), rosetting with uninfected erythrocytes and platelet-mediated clumping of infected erythrocytes. Recent research has started to define the molecular mechanisms of parasite adhesion, and antiadhesion therapies are being explored. However, many fundamental questions regarding the role of parasite adhesion in severe malaria remain unanswered. There is strong evidence that rosetting contributes to severe malaria in sub-Saharan Africa; however, the identity of other parasite adhesion phenotypes that are implicated in disease pathogenesis remains unclear. In addition, the possibility of geographic variation in adhesion phenotypes causing severe malaria, linked to differences in malaria transmission levels and host immunity, has been neglected. Further research is needed to realise the untapped potential of antiadhesion adjunctive therapies, which could revolutionise the treatment of severe malaria and reduce the high mortality rate of the disease.

scholarly journals Successful and Unsuccessful Brain Aging in Pets: Pathophysiological Mechanisms behind Clinical Signs and Potential Benefits from Palmitoylethanolamide Nutritional Intervention

Animals ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2584
Author(s):  
Caterina Scuderi ◽  
Lorenzo Golini
Keyword(s):  
Molecular Mechanisms ◽  
Brain Aging ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Clinical Signs ◽  
Endocannabinoid System ◽  
Nutritional Intervention ◽  
Underlying Disease ◽  
Age Related ◽  
Ultramicronized Palmitoylethanolamide

Canine and feline cognitive dysfunction syndrome is a common neurodegenerative disorder of old age and a natural model of human Alzheimer’s disease. With the unavoidable expanding life expectancy, an increasing number of small animals will be affected. Although there is no cure, early detection and intervention are vitally important to delay cognitive decline. Knowledge of cellular and molecular mechanisms underlying disease onset and progression is an equally decisive factor for developing effective approaches. Uncontrolled neuroinflammation, orchestrated in the central nervous system mainly by astrocytes, microglia, and resident mast cells, is currently acknowledged as a hallmark of neurodegeneration. This has prompted scientists to find a way to rebalance the altered crosstalk between these cells. In this context, great emphasis has been given to the role played by the expanded endocannabinoid system, i.e., endocannabinoidome, because of its prominent role in physiological and pathological neuroinflammation. Within the endocannabinoidome, great attention has been paid to palmitoylethanolamide due to its safe and pro-homeostatic effects. The availability of new ultramicronized formulations highly improved the oral bioavailability of palmitoylethanolamide, paving the way to its dietary use. Ultramicronized palmitoylethanolamide has been repeatedly tested in animal models of age-related neurodegeneration with promising results. Data accumulated so far suggest that supplementation with ultramicronized palmitoylethanolamide helps to accomplish successful brain aging.

scholarly journals W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34

2021 ◽  
Author(s):  
Raghavendra Nagaraja ◽  
David Sherry ◽  
Jennifer Fessler ◽  
Megan Stiles ◽  
Feng Li ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Rat Model ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Long Term Potentiation ◽  
Motor Deficits ◽  
Spinocerebellar Ataxias ◽  
Fatty Acid Elongase ◽  
Age Related

Abstract Spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders caused by a number of different mutations the leads to loss of motor coordination with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is an age-related cerebellar neurodegenerative disorder caused by mutations in the Fatty Acid Elongase-4 (ELOVL4). The ELOVL4 is an essential enzyme that mediates biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons) that are critical for the normal function of brain, skin, retina, Meibomian glands, and testes in which ELOVL4 is expressed. Global deletion or homozygous expression of truncated mutant ELOVL4 that lack VLC-SFA and VLC-PUFA biosynthesis cause severe skin disorders, seizures and neonatal mortality in rodents and humans. To understand the consequences of ELOVL4 mutations in pathogenesis of SCA34, we generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. We show that heterozygous and homozygous rats carrying the W246G mutation developed impaired motor deficits by two months of age. Our electrophysiological studies using cerebellar slices found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells in the homozygous W246G mutant rats. Our results further point to ELOVL4 products as being essential for motor function and cerebellar synaptic plasticity. These results suggest that in SCA34 patients, ataxia likely arises from primary impairment of synaptic plasticity and cerebellar network desynchronization that precedes cerebellar degeneration and loss of motor coordination with aging.

Neuroprotective Effects of Ellagic Acid in Alzheimer's Disease: Focus on Underlying Molecular Mechanisms of Therapeutic Potential

2020 ◽  
Vol 26 ◽  
Author(s):  
Nimra Javaid ◽  
Muhammad Ajmal Shah ◽  
Azhar Rasul ◽  
Zunera Chauhdary ◽  
Uzma Saleem ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Ellagic Acid ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Acetylcholinesterase Activity ◽  
Neuroprotective Effects

: Neurodegeneration is a multifactorial process involved the different cytotoxic pathways that lead towards neuronal cell death. Alzheimer’s disease (AD) is a persistent neurodegenerative disorder that normally has a steady onset yet later on it worsens. The documented evidence of AD neuropathology manifested the neuro-inflammation, increased reactive oxygen, nitrogen species and decreased antioxidant protective process; mitochondrial dysfunction as well as increased level of acetylcholinesterase activity. Moreover, enhanced action of proteins leads towards neural apoptosis which have a vital role in the degeneration of neurons. The inability of commercial therapeutic options to treat AD with targeting single mechanism leads the attraction towards organic drugs. Ellagic acid is a dimer of gallic acid, latest studies expressed that ellagic acid can initiate the numerous cell signaling transmission and decrease the progression of disorders, involved in the degeneration of neurons. The influential property of ellagic acid to protect the neurons in neurodegenerative disorders is due to its antioxidant effect, iron chelating and mitochondrial protective effect. The main goal of this review is to critically analyze the molecular mode of action of ellagic acid against neurodegeneration.

scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

scholarly journals Endothelial activation and dysfunction in COVID-19: from basic mechanisms to potential therapeutic approaches

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Yuefei Jin ◽  
Wangquan Ji ◽  
Haiyan Yang ◽  
Shuaiyin Chen ◽  
Weiguo Zhang ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Endothelial Activation ◽  
World Health ◽  
Therapeutic Approaches ◽  
Inflammatory Reactions ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Implications ◽  
Endothelial Inflammation ◽  
The World ◽  
Health Organization

AbstractOn 12 March 2020, the outbreak of coronavirus disease 2019 (COVID-19) was declared a pandemic by the World Health Organization. As of 4 August 2020, more than 18 million confirmed infections had been reported globally. Most patients have mild symptoms, but some patients develop respiratory failure which is the leading cause of death among COVID-19 patients. Endothelial cells with high levels of angiotensin-converting enzyme 2 expression are major participants and regulators of inflammatory reactions and coagulation. Accumulating evidence suggests that endothelial activation and dysfunction participate in COVID-19 pathogenesis by altering the integrity of vessel barrier, promoting pro-coagulative state, inducing endothelial inflammation, and even mediating leukocyte infiltration. This review describes the proposed cellular and molecular mechanisms of endothelial activation and dysfunction during COVID-19 emphasizing the principal mediators and therapeutic implications.

scholarly journals Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Tsui-Wen Chou ◽  
Nydia P. Chang ◽  
Medha Krishnagiri ◽  
Aisha P. Patel ◽  
Marissa Lindman ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Dopamine Neurons ◽  
Functional Markers ◽  
Kinase Signaling ◽  
Astrocyte Activation ◽  
Transcriptional Responses

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by the death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of the disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

scholarly journals Neuropathology of the Brainstem to Mechanistically Understand and to Treat Alzheimer’s Disease

2021 ◽  
Vol 10 (8) ◽  
pp. 1555
Author(s):  
Ágoston Patthy ◽  
János Murai ◽  
János Hanics ◽  
Anna Pintér ◽  
Péter Zahola ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Brain Structures ◽  
Specific Information ◽  
Cellular Mechanisms ◽  
Monoaminergic System ◽  
Monoaminergic Neurons

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder as yet without effective therapy. Symptoms of this disorder typically reflect cortical malfunction with local neurohistopathology, which biased investigators to search for focal triggers and molecular mechanisms. Cortex, however, receives massive afferents from caudal brain structures, which do not only convey specific information but powerfully tune ensemble activity. Moreover, there is evidence that the start of AD is subcortical. The brainstem harbors monoamine systems, which establish a dense innervation in both allo- and neocortex. Monoaminergic synapses can co-release neuropeptides either by precisely terminating on cortical neurons or, when being “en passant”, can instigate local volume transmission. Especially due to its early damage, malfunction of the ascending monoaminergic system emerges as an early sign and possible trigger of AD. This review summarizes the involvement and cascaded impairment of brainstem monoaminergic neurons in AD and discusses cellular mechanisms that lead to their dysfunction. We highlight the significance and therapeutic challenges of transmitter co-release in ascending activating system, describe the role and changes of local connections and distant afferents of brainstem nuclei in AD, and summon the rapidly increasing diagnostic window during the last few years.

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