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Author: Eric Anderson Publisher: ISBN: Category : Languages : en Pages : 167
Book Description
The intracellular transport of protein complexes, membrane-bound vesicles, organelles, and RNA along microtubule (MT) tracks to the axonal terminal is crucial for neuronal survival and function. In neurodegenerative disorders, such as Parkinson's disease (PD), defects in the axonal transport pathway are suggested to be major contributors to neurodegeneration. a-syn (a-syn) is a small acid protein that is actively transported from the cell body to the axonal terminal and is the main constituent of Lewy bodies (LB), abnormal deposits of protein in the brain in PD. In my dissertation research, I have focused on the mechanism of a-syn transport in axons. The effects of familial PD (fPD) mutations on the transport of a-syn and synaptic proteins were also studied using Drosophila melanogaster (fruit flies) as a model organism. I have found that the aggregate-prone non-amyloidal component (NAC) region in a-syn was required for the dimerization and membrane binding for a-syn during its transport to the axonal terminal. Deletion of a-syn NAC region (delNAC) resulted in an increase in its accumulation within cell bodies located in the brain, decreased its entry into axons, and its transport to the axonal terminal. This decrease in the transport of delNAC to the axonal terminal is due to decreased membrane interaction of a-syn. I have also demonstrated that increased levels of a-syn (3-fold increase mimicking gene triplication in PD or fPD mutation (Alanine53Threoine, A53T)) accumulation in axons disrupt the axonal transport of synaptic proteins, resulting in synaptic morphological defects and locomotion behavior defects. This accumulation of Îł-syn in axons is likely due to dimerization of Îł-syn through the NAC region, possibly on membranes. Therefore, this part of the study revealed an important role for the NAC region in mediating a-syn dimerization on membranes for a-syn transport to the axonal terminal. The second part of the study focused on the effects of a-syn on Rab3 motility. The Rab3 protein, a neuronal guanosine triphosphate (GTP)-binding protein, has been proposed to present together with a-syn on vesicles and has a similar function in regulating synaptic vesicle trafficking. In vivo live image analysis showed disruption of Rab3 motility with excess or fPD mutant a-syn, and mutant Rab3 disrupted the transport of a-syn-containing vesicle to the axonal terminal. Thus, this study highlights, for the first time, a potential interaction between Rab3 and a-syn in the axonal transport pathway. Collectively, these studies provided new insights into our understanding of the a-syn protein in the axonal transport pathway. Alteration in the axonal transport pathway can have important implications in PD, thus, elucidating the mechanism of a-syn protein transport and Îł-syn-mediated disruption of the axonal transport pathway is critical to our overall understanding of the contribution of this pathway to the disease progression.
Author: Eric Anderson Publisher: ISBN: Category : Languages : en Pages : 167
Book Description
The intracellular transport of protein complexes, membrane-bound vesicles, organelles, and RNA along microtubule (MT) tracks to the axonal terminal is crucial for neuronal survival and function. In neurodegenerative disorders, such as Parkinson's disease (PD), defects in the axonal transport pathway are suggested to be major contributors to neurodegeneration. a-syn (a-syn) is a small acid protein that is actively transported from the cell body to the axonal terminal and is the main constituent of Lewy bodies (LB), abnormal deposits of protein in the brain in PD. In my dissertation research, I have focused on the mechanism of a-syn transport in axons. The effects of familial PD (fPD) mutations on the transport of a-syn and synaptic proteins were also studied using Drosophila melanogaster (fruit flies) as a model organism. I have found that the aggregate-prone non-amyloidal component (NAC) region in a-syn was required for the dimerization and membrane binding for a-syn during its transport to the axonal terminal. Deletion of a-syn NAC region (delNAC) resulted in an increase in its accumulation within cell bodies located in the brain, decreased its entry into axons, and its transport to the axonal terminal. This decrease in the transport of delNAC to the axonal terminal is due to decreased membrane interaction of a-syn. I have also demonstrated that increased levels of a-syn (3-fold increase mimicking gene triplication in PD or fPD mutation (Alanine53Threoine, A53T)) accumulation in axons disrupt the axonal transport of synaptic proteins, resulting in synaptic morphological defects and locomotion behavior defects. This accumulation of Îł-syn in axons is likely due to dimerization of Îł-syn through the NAC region, possibly on membranes. Therefore, this part of the study revealed an important role for the NAC region in mediating a-syn dimerization on membranes for a-syn transport to the axonal terminal. The second part of the study focused on the effects of a-syn on Rab3 motility. The Rab3 protein, a neuronal guanosine triphosphate (GTP)-binding protein, has been proposed to present together with a-syn on vesicles and has a similar function in regulating synaptic vesicle trafficking. In vivo live image analysis showed disruption of Rab3 motility with excess or fPD mutant a-syn, and mutant Rab3 disrupted the transport of a-syn-containing vesicle to the axonal terminal. Thus, this study highlights, for the first time, a potential interaction between Rab3 and a-syn in the axonal transport pathway. Collectively, these studies provided new insights into our understanding of the a-syn protein in the axonal transport pathway. Alteration in the axonal transport pathway can have important implications in PD, thus, elucidating the mechanism of a-syn protein transport and Îł-syn-mediated disruption of the axonal transport pathway is critical to our overall understanding of the contribution of this pathway to the disease progression.
Author: Savannah YT Fang Publisher: ISBN: Category : Languages : en Pages : 49
Book Description
Parkinson's Disease (PD) is the second most common neurodegenerative disease, which is characterized by the loss of dopaminergic neurons in the substantia nigra of the brain possibly due to the accumulation of [alpha]-synuclein (ASYN). Mutations or triplication of the ASYN gene (SNCA) contribute to synucleinopathies including PD, but studies have also noted that a significant portion of PD patients develop Alzheimer's Disease (AD) like dementia. Therefore, we hypothesized that excessive accumulation of ASYN may also impact the trafficking and processing of the amyloid precursor protein (APP), initiating the pathogenesis of AD. To test our hypothesis, we used a transgenic mouse model of PD that over-expresses a green fluorescent protein fused human ASYN (GFP-hASYN) transgene. Our findings suggest that the over-expression of GFP-hASYN in mouse neurons i.e. PD neurons impaired axonal trafficking and processing of APP. Furthermore, APP carboxyl terminal fragment (APP CTF) levels were significantly higher in GFP-hASYN+ positive PD neurons than in GFP-hASYN- neurons, suggesting impairment in downstream processes. Interestingly, in ASYN knockout (SynKO) neurons, APP trafficking and processing was largely unaffected as compared to wildtype (WT) neurons'. Based on these observations, we speculate that selective impairment of trafficking and processing of APP by ASYN may give rise to toxic CTFs, which may contribute to blockages, leading to endosomal enlargement, axonal transport impairment and eventually neuronal atrophy. This study provides an important molecular mechanism by which excessive accumulation of ASYN could potentially be linked to cellular events that lead to AD pathogenesis in addition to its role in inducing neurotoxicity in PD pathology.
Author: Leslie L. Iversen Publisher: ISBN: 0195373030 Category : Medical Languages : en Pages : 632
Book Description
The discovery of dopamine in 1957-1958 was one of the seminal events in the development of modern neuroscience, and has been extremely important for the development of modern therapies of neurological and psychiatric disorders. Dopamine has a fundamental role in almost all aspects of behavior: from motor control to mood regulation, cognition and addiction and reward, and dopamine research has been unique within the neurosciences in the way it has bridged basic science and clinical practice. Over the decades research into the role of dopamine in health and disease has been in the forefront of modern neuroscience. The Dopamine Handbook is the first single-volume publication to capture current progress and excitement in this dynamic research field.
Author: Heiko Braak Publisher: Springer ISBN: 9783540798491 Category : Medical Languages : en Pages : 119
Book Description
The synucleinopathy sporadic Parkinson’s disease (sPD) is the second most frequent degenerative disorder of the human nervous system after Alzheimer’s disease. The propensity for developing sPD exists in all ethnic groups worldwide, and the prevalence of the disorder increases considerably with age, thereby imposing an enormous social and economic burden on societies with increased life expectancy. The sPD-associated pathological process is progressive, does not go into remission, and can take decades to reach its culmination if it is not be terminated prematurely by death owing to other causes. Against the background of the normal morphology and anatomy, the authors analyze the pathoanatomy of sPD in the nervous system at various neuropathological stages and summarize the potential functional consequences of the lesions.
Author: Jonas H. Ellenberg Publisher: CRC Press ISBN: 9780824788230 Category : Medical Languages : en Pages : 600
Book Description
This comprehensive reference provides a detailed overview of current concepts regarding the cause of Parkinson's disease-emphasizing the issues involved in the design, implementation, and analysis of epidemiological studies of parkinsonism.
Author: Laura Lossi Publisher: Humana Press ISBN: 9781493921515 Category : Medical Languages : en Pages : 0
Book Description
This volume represents a valuable and readily reproducible collection of established and emerging techniques for neuronal cell death research. Conveniently divided into four parts, sections cover a series of techniques for the molecular, structural, functional and genomic characterization of dying neurons, a number of protocols that are of primary interest in neuropathology and in experimental neuropathology, a series of gene engineering techniques to obtain and manipulate neuronal stem cells and progenitors, to prepare HSV-1 vectors for the gene therapy, and to CNS transplantation of bone marrow stem cells, and finally, some very interesting protocols for the study of cell death in non-mammalian models. Written in the successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible protocols, and notes on troubleshooting and avoiding known pitfalls. Authoritative and easily accessible, Neuronal Cell Death: Methods and Protocols seeks to serve a large audience of scientists that are currently active in the field or are willing to enter such an exciting and still expanding area of neurobiology.
Author: Shamim I. Ahmad Publisher: Springer Science & Business Media ISBN: 1461406536 Category : Medical Languages : en Pages : 421
Book Description
The editor of this volume, having research interests in the field of ROS production and the damage to cellular systems, has identified a number of enzymes showing ·OH scavenging activities details of which are anticipated to be published in the near future as confirmatory experiments are awaited. It is hoped that the information presented in this book on NDs will stimulate both expert and novice researchers in the field with excellent overviews of the current status of research and pointers to future research goals. Clinicians, nurses as well as families and caregivers should also benefit from the material presented in handling and treating their specialised cases. Also the insights gained should be valuable for further understanding of the diseases at molecular levels and should lead to development of new biomarkers, novel diagnostic tools and more effective therapeutic drugs to treat the clinical problems raised by these devastating diseases.
Author: Hardy J. Rideout Publisher: Springer ISBN: 3319499696 Category : Medical Languages : en Pages : 280
Book Description
This is the first book to assemble the leading researchers in the field of LRRK2 biology and neurology and provide a snapshot of the current state of knowledge, encompassing all major aspects of its function and dysfunction. The contributors are experts in cell biology and physiology, neurobiology, and medicinal chemistry, bringing a multidisciplinary perspective on the gene and its role in disease. The book covers the identification of LRRK2 as a major contributor to the pathogenesis of Parkinson's Disease. It also discusses the current state of the field after a decade of research, putative normal physiological roles of LRRK2, and the various pathways that have been identified in the search for the mechanism(s) of its induction of neurodegeneration.
Author: Lawrence H. Lash Publisher: Elsevier ISBN: 1483218619 Category : Science Languages : en Pages : 527
Book Description
Methods in Toxicology, Volume 2: Mitochondrial Dysfunction provides a source of methods, techniques, and experimental approaches for studying the role of abnormal mitochondrial function in cell injury. The book discusses the methods for the preparation and basic functional assessment of mitochondria from liver, kidney, muscle, and brain; the methods for assessing mitochondrial dysfunction in vivo and in intact organs; and the structural aspects of mitochondrial dysfunction are addressed. The text also describes chemical detoxification and metabolism as well as specific metabolic reactions that are especially important targets or indicators of damage. The methods for measurement of alterations in fatty acid and phospholipid metabolism and for the analysis and manipulation of oxidative injury and antioxidant systems are also considered. The book further tackles additional methods on mitochondrial energetics and transport processes; approaches for assessing impaired function of mitochondria; and genetic and developmental aspects of mitochondrial disease and toxicology. The text also looks into mitochondrial DNA synthesis, covalent binding to mitochondrial DNA, DNA repair, and mitochondrial dysfunction in the context of developing individuals and cellular differentiation. Microbiologists, toxicologists, biochemists, and molecular pharmacologists will find the book invaluable.
Author: Eric Anderson
Author: Eric Anderson![Accumulation of [alpha]-Synuclein Impairs Trafficking and Processing of Amyloid Precursor Protein in a Mouse Model of Parkinson's Disease PDF](https://books.google.com/books/content/images/frontcover/QQ-yzQEACAAJ?fife=w80-h100)
Author: Savannah YT Fang
Author: Leslie L. Iversen
Author: Heiko Braak
Author: Jonas H. Ellenberg
Author: Laura Lossi
Author: Shamim I. Ahmad
Author: John Barton Furness
Author: Hardy J. Rideout
Author: Lawrence H. Lash