[PDF] The Protein Alpha Synuclein Its Normal Role In Neurons And Its Role In Disease eBook

Author : Jonas H. Ellenberg
Publisher : CRC Press
Page : 600 pages
File Size : 18,26 MB
Release : 1995-03-01
Category : Medical
ISBN : 9780824788230

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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 : Malcolm D. Anthony
Publisher :
Page : 122 pages
File Size : 38,63 MB
Release : 2006
Category :
ISBN :

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The synaptic protein alpha-synuclein is implicated in pathogenesis of Parkinson's disease (PD) and other neurodegenerative disorders. In PD alpha-synuclein accumulates abnormally and is the main component of Lewy bodies. The normal function of alpha-synuclein remains ambiguous and its role in PD is not well understood. I chose to characterize the structure and function of alpha-synuclein with aims of elucidating its role at the synapse and understanding the context for its toxicity in PD. Although association with synaptic vesicles appears important for the localization of alpha-synuclein to presynaptic terminals, alpha-synuclein behaves primarily as a soluble protein in brain extracts. However, synaptic localization of the protein requires the membrane-binding amino-terminal repeat region, but the role of the C-terminus is not clear. Within its C-terminus, alpha-synuclein is phosphorylated at Ser-129, and the protein is found highly phosphorylated at Ser-129 in the Lewy bodies of PD. To determine whether phosphorylation affects synaptic localization of alpha-synuclein, I made mutations to mimic or block phosphorylation within the C-terminal domain. Using live cell imaging in combination with fluorescence photobleaching recovery, I investigated the role of phosphorylation in the mobility of the protein at the synapse. I find mutations that affect phosphorylation of alpha-synuclein within its C-terminus do not affect either synaptic localization or recovery time; however, a mutation that blocks phosphorylation of Ser-129 reduces the mobile fraction of protein. The decrease in mobile fraction indicates the protein could be interacting in a stable manner with components of the synapse, and this was confirmed by sequential photobleaching. No effect was found for other mutations. Thus phosphorylation at Ser-129, which appears increasingly important in PD, regulates alpha-synuclein binding to elements of the nerve terminal.

Author : Laura Lossi
Publisher : Humana Press
Page : 0 pages
File Size : 23,52 MB
Release : 2014-11-28
Category : Medical
ISBN : 9781493921515

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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
Page : 421 pages
File Size : 17,44 MB
Release : 2012-03-12
Category : Medical
ISBN : 1461406536

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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 : Colin R Martin
Publisher : Academic Press
Page : 764 pages
File Size : 18,34 MB
Release : 2020-08-13
Category : Medical
ISBN : 0128159510

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Genetics, Neurology, Behavior, and Diet in Parkinson's Disease: The Neuroscience of Parkinson’s Disease, Volume 2 provides a single source of material covering different scientific domains of neuropathology underlying this condition. The book covers a wide range of subjects and unravels the complex relationships between genetics, molecular biology, pharmaceutical chemistry, neurobiology, imaging, assessments, and treatment regimens. It fills a much-needed gap as a "one-stop" synopsis of everything to do with the neurology and neuroscience related to Parkinson’s disease—from chemicals and cells to individuals. It is an invaluable resource for neuroscientists, neurologists, and anyone in the field. Offers the most comprehensive coverage of a broad range of topics related to Parkinson's disease Serves as a foundational collection for neuroscientists and neurologists on the biology of disease and brain dysfunction Contains in each chapter an abstract, key facts, mini dictionary of terms, and summary points to aid in understanding Features preclinical and clinical studies to help researchers map out key areas for research and further clinical recommendations Serves as a "one-stop" source for everything you need to know about Parkinson’s disease

Author : Jesus Avila
Publisher : Frontiers E-books
Page : 114 pages
File Size : 42,9 MB
Release : 2014-08-18
Category : Medicine (General)
ISBN : 288919261X

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Neurofibrillary tangles (NFTs) composed of intracellular aggregates of tau protein are a key neuropathological feature of Alzheimer’s Disease (AD) and other neurodegenerative diseases, collectively termed tauopathies. The abundance of NFTs has been reported to correlate positively with the severity of cognitive impairment in AD. However, accumulating evidences derived from studies of experimental models have identified that NFTs themselves may not be neurotoxic. Now, many of tau researchers are seeking a “toxic” form of tau protein. Moreover, it was suggested that a “toxic” tau was capable to seed aggregation of native tau protein and to propagate in a prion-like manner. However, the exact neurotoxic tau species remain unclear. Because mature tangles seem to be non-toxic component, “tau oligomers” as the candidate of “toxic” tau have been investigated for more than one decade. In this topic, we will discuss our consensus of “tau oligomers” because the term of “tau oligomers” [e.g. dimer (disulfide bond-dependent or independent), multimer (more than dimer), granular (definition by EM or AFM) and maybe small filamentous aggregates] has been used by each researchers definition. From a biochemical point of view, tau protein has several unique characteristics such as natively unfolded conformation, thermo-stability, acid-stability, and capability of post-translational modifications. Although tau protein research has been continued for a long time, we are still missing the mechanisms of NFT formation. It is unclear how the conversion is occurred from natively unfolded protein to abnormally mis-folded protein. It remains unknown how tau protein can be formed filaments [e.g. paired helical filament (PHF), straight filament and twisted filament] in cells albeit in vitro studies confirmed tau self-assembly by several inducing factors. Researchers are still debating whether tau oligomerization is primary event rather than tau phosphorylation in the tau pathogenesis. Inhibition of either tau phosphorylation or aggregation has been investigated for the prevention of tauopathies, however, it will make an irrelevant result if we don’t know an exact target of neurotoxicity. It is a time to have a consensus of definition, terminology and methodology for the identification of “tau oligomers”.

Author : Margaret M. Esiri
Publisher : Cambridge University Press
Page : 600 pages
File Size : 24,37 MB
Release : 2004-07-22
Category : Medical
ISBN : 9780521819152

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Completely rewritten and updated, this new edition is almost twice the size of its predecessor. Illustrated in colour throughout, and with contributions from the world's leading authorities, it is the definitive reference on the neuropathology of dementia. It gives practical guidance to pathologists, describes the contribution of neuroimaging to diagnosis, and surveys the clinical features of dementia. New material includes: Three entirely new chapters on neuroimaging, molecular diagnostics, and transgenic models. Two chapters on tauopathies under new authorship. A chapter under new authorship on synucleinopathies, which includes multiple system atrophy.

Author : TaeHee Kim
Publisher :
Page : 0 pages
File Size : 11,38 MB
Release : 2017
Category :
ISBN :

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Parkinson's disease (PD) and stroke are debilitating conditions that result in neuronal death and loss of neurological functions. These two conditions predominantly affect aging populations with the deterioration of the quality of life of patients and a tremendous burden to families. While the neurodegeneration and symptomology of PD develop chronically over the years, post-stroke neuronal death and dysfunction develop rapidly in days. Despite the discrepancy in the pathophysiological time frame and severity, both conditions share common molecular mechanisms that include mitochondrial dysfunction, oxidative stress, inflammation, endoplasmic reticulum stress, and activation of various cell death pathways (apoptosis/necrosis/autophagy) that synergistically modulate neurodegeneration. Emerging evidence indicates that [alpha]-synuclein ([alpha]-Syn) plays a critical role in the PD-induced brain damage. Our lab identified that [alpha]-Syn is also induced rapidly in the brain following ischemic stroke. However, the pathophysiological role of [alpha]-Syn and its up- and downstream mechanisms after ischemic stroke are not clear. In Chapter 1, I comprehensively discussed how [alpha]-Syn and other chronic neurodegeneration-related proteins are related in common mechanisms that lead to brain damage after PD and stroke. In Chapter 2, I presented the evidence to show that [alpha]-Syn mediates post-stroke brain damage. My studies show that transient focal ischemia upregulates [alpha]-Syn protein expression and nuclear translocation in neurons of the adult rodent brain. I also showed that [alpha]-Syn protein also undergoes aggregation in the post-ischemic brain. I further demonstrated that knockdown or knockout of [alpha]-Syn significantly decreases the infarction and promotes better neurological functional recovery in rodents subjected to focal ischemia. Furthermore, [alpha]-Syn knockdown significantly reduced post-ischemic induction of phospho-Drp1 (pDrp1), 3-nitrotyrosine, cleaved caspase-3 and LC-3 II/I indicating its role in modulating mitochondrial fragmentation, oxidative stress, apoptosis and autophagy which are known to mediate post-stroke neuronal death. Transient focal ischemia also significantly upregulated serine-129 (S129) phosphorylation of [alpha]-Syn (p[alpha]-Syn) and nuclear translocation of p[alpha]-Syn. Furthermore, knockout mice that lack PLK2 (the predominant kinase that mediates S129 phosphorylation) showed better functional recovery and smaller infarcts when subjected to transient focal ischemia indicating a detrimental role of S129 phosphorylation of [alpha]-Syn. In conclusion, these studies indicate that [alpha]-Syn is a potential therapeutic target to minimize post-stroke brain damage. Over the past decade, microRNAs (miRNAs) have emerged as important regulators of translation and thus modulators of cellular signaling. These small non-coding RNAs act at the post-transcriptional level by targeting the 3'-untranslated region (UTR) of mRNAs, resulting in translational repression or degradation of target mRNAs. Using in silico analysis, we identified that [alpha]-Syn is a potential target of the miRNA miR-7a-5p (miR-7). Our lab previously showed that miR-7 is one of the miRNAs down-regulated in rodent brain in a sustained manner during the acute phase (1 to 3 days) after focal ischemia. The miR-7 has also been reported to ameliorate cellular stress by suppressing [alpha]-Syn expression levels in an in vitro PD model. However, the role and underlying mechanisms of miR-7 in cerebral ischemia is currently unknown. In Chapter 3, I focused on the mechanistic connection between miR-7 down-regulation and de-repression of [alpha]-Syn expression after ischemia. Using 3-UTR vectors, my studies show that [alpha]-Syn is a target of miR-7. I further show that miR-7 is a regulator of post-ischemic [alpha]-Syn expression, and replenishing miR-7 levels decreases [alpha]-Syn levels and protect the brain after focal cerebral ischemia. Treatment with miR-7 mimic decreased infarct volume as well as led to a better recovery of neurological function after focal ischemia. Importantly, I show that miR-7 mimic therapy is neuroprotective in both male and female rodents at young and aged conditions. Thus, data present in this chapter suggests a novel opportunity to control [alpha]-Syn levels and protect the brain after a stroke by replenishing miR-7 levels.