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Intracellular Inclusions (intracellular + inclusion)
Selected AbstractsThe solubility of ,-synuclein in multiple system atrophy differs from that of dementia with Lewy bodies and Parkinson's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 1 2001Bruce C. V. Campbell Intracellular inclusions containing ,-synuclein (,SN) are pathognomonic features of several neurodegenerative disorders. Inclusions occur in oligodendrocytes in multiple system atrophy (MSA) and in neurons in dementia with Lewy bodies (DLB) and Parkinson's disease (PD). In order to identify disease-associated changes of ,SN, this study compared the levels, solubility and molecular weight species of ,SN in brain homogenates from MSA, DLB, PD and normal aged controls. In DLB and PD, substantial amounts of detergent-soluble and detergent-insoluble ,SN were detected compared with controls in grey matter homogenate. Compared with controls, MSA cases had significantly higher levels of ,SN in the detergent-soluble fraction of brain samples from pons and white matter but detergent-insoluble ,SN was not detected. There was an inverse correlation between buffered saline-soluble and detergent-soluble levels of ,SN in individual MSA cases suggesting a transition towards insolubility in disease. The differences in solubility of ,SN between grey and white matter in disease may result from different processing of ,SN in neurons compared with oligodendrocytes. Highly insoluble ,SN is not involved in the pathogenesis of MSA. It is therefore possible that buffered saline-soluble or detergent-soluble forms of ,SN are involved in the pathogenesis of other ,SN-related diseases. [source] In vivo gene delivery of glial cell line,derived neurotrophic factor for Parkinson's diseaseANNALS OF NEUROLOGY, Issue S3 2003Jeffrey H. Kordower PhD Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects approximately 1,000,000 Americans. The cause of the disease remains unknown. The histopathological hallmarks of the disease are dopaminergic striatal insufficiency secondary to a loss of dopaminergic neurons in the substantia nigra pars compacta and intracellular inclusion called Lewy bodies. Currently, only symptomatic treatment for PD is available. Although some treatments are efficacious for many years, all have significant limitations and new therapeutic approaches are needed. Gene therapy is ideal for delivering therapeutic molecules to site-specific regions of the central nervous system. Via gene therapy, a piece or pieces of DNA placed into a carrying vector encoding for a substance of interest can be introduced into specific cells. Although there are several ways that gene therapy can be applied for PD, this review focuses on in vivo gene delivery of glial cell line,derived neurotrophic factor (GDNF) as a neuroprotective strategy for PD. Ann Neurol 2003;53 (suppl 3):S120,S134 [source] Mechanisms and consequences of bladder cell invasion by uropathogenic Escherichia coliEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 2008B. K. Dhakal ABSTRACT Strains of uropathogenic Escherichia coli (UPEC) are the major cause of urinary tract infections worldwide. Multiple studies over the past decade have called into question the dogmatic view that UPEC strains act as strictly extracellular pathogens. Rather, bacterial expression of filamentous adhesive organelles known as type 1 pili and Afa/Dr fibrils enable UPEC to invade host epithelial cells within the urinary tract. Entry into bladder epithelial cells provides UPEC with a protected niche where the bacteria can persist quiescently for long periods, unperturbed by host defences and protected from many antibiotic treatments. Alternately, internalized UPEC can rapidly multiply, forming large intracellular inclusions that can contain several thousand bacteria. Initial work aimed at defining the host and bacterial factors that modulate the entry, intracellular trafficking, and eventual resurgence of UPEC suggests a high degree of host-pathogen crosstalk. Targeted disruption of these processes may provide a novel means to prevent and treat recurrent, relapsing and chronic infections within the urinary tract. [source] Protein misfolding inside cells: The case of huntingtin and Huntington's diseaseIUBMB LIFE, Issue 11 2008Danny M. Hatters Abstract Huntington's disease is one of the several neurodegenerative diseases caused by dominant mutations that expand the number of glutamine codons within an existing poly-glutamine (polyQ) repeat sequence of a gene. An expanded polyQ sequence in the huntingtin gene is known to cause the huntingtin protein to aggregate and form intracellular inclusions as disease progresses. However, the role that polyQ-induced aggregation plays in disease is yet to be fully determined. This review focuses on key questions remaining for how the expanded polyQ sequences affect the aggregation properties of the huntingtin protein and the corresponding effects on cellular machinery. The scope includes the technical challenges that remain for rigorously assessing the effects of aggregation on the cellular machinery. © 2008 IUBMB IUBMB Life, 60(11): 724,728, 2008 [source] ,-Synuclein modulation of Ca2+ signaling in human neuroblastoma (SH-SY5Y) cellsJOURNAL OF NEUROCHEMISTRY, Issue 5 2009Nishani T. Hettiarachchi Abstract Parkinson's disease (PD) is characterized in part by the presence of ,-synuclein (,-syn) rich intracellular inclusions (Lewy bodies). Mutations and multiplication of the ,-synuclein gene (SNCA) are associated with familial PD. Since Ca2+ dyshomeostasis may play an important role in the pathogenesis of PD, we used fluorimetry in fura-2 loaded SH-SY5Y cells to monitor Ca2+ homeostasis in cells stably transfected with either wild-type ,-syn, the A53T mutant form, the S129D phosphomimetic mutant or with empty vector (which served as control). Voltage-gated Ca2+ influx evoked by exposure of cells to 50 mM K+ was enhanced in cells expressing all three forms of ,-syn, an effect which was due specifically to increased Ca2+ entry via L-type Ca2+ channels. Mobilization of Ca2+ by muscarine was not strikingly modified by any of the ,-syn forms, but they all reduced capacitative Ca2+ entry following store depletion caused either by muscarine or thapsigargin. Emptying of stores with cyclopiazonic acid caused similar rises of [Ca2+]i in all cells tested (with the exception of the S129D mutant), and mitochondrial Ca2+ content was unaffected by any form of ,-synuclein. However, only WT ,-syn transfected cells displayed significantly impaired viability. Our findings suggest that ,-syn regulates Ca2+ entry pathways and, consequently, that abnormal ,-syn levels may promote neuronal damage through dysregulation of Ca2+ homeostasis. [source] What determines the molecular composition of abnormal protein aggregates in neurodegenerative disease?NEUROPATHOLOGY, Issue 4 2008Richard A. Armstrong Abnormal protein aggregates, in the form of either extracellular plaques or intracellular inclusions, are an important pathological feature of the majority of neurodegenerative disorders. The major molecular constituents of these lesions, viz., ,-amyloid (A,), tau, and ,-synuclein, have played a defining role in the diagnosis and classification of disease and in studies of pathogenesis. The molecular composition of a protein aggregate, however, is often complex and could be the direct or indirect consequence of a pathogenic gene mutation, be the result of cell degeneration, or reflect the acquisition of new substances by diffusion and molecular binding to existing proteins. This review examines the molecular composition of the major protein aggregates found in the neurodegenerative diseases including the A, and prion protein (PrP) plaques found in Alzheimer's disease (AD) and prion disease, respectively, and the cellular inclusions found in the tauopathies and synucleinopathies. The data suggest that the molecular constituents of a protein aggregate do not directly cause cell death but are largely the consequence of cell degeneration or are acquired during the disease process. These findings are discussed in relation to diagnosis and to studies of to disease pathogenesis. [source] What does the study of the spatial patterns of pathological lesions tell us about the pathogenesis of neurodegenerative disorders?NEUROPATHOLOGY, Issue 1 2001Richard A Armstrong Discrete pathological lesions, which include extracellular protein deposits, intracellular inclusions and changes in cell morphology, occur in the brain in the majority of neurodegenerative disorders. These lesions are not randomly distributed in the brain but exhibit a spatial pattern, that is, a departure from randomness towards regularity or clustering. The spatial pattern of a lesion may reflect pathological processes affecting particular neuroanatomical structures and, therefore, studies of spatial pattern may help to elucidate the pathogenesis of a lesion and of the disorders themselves. The present article reviews first, the statistical methods used to detect spatial patterns and second, the types of spatial patterns exhibited by pathological lesions in a variety of disorders which include Alzheimer's disease, Down syndrome, dementia with Lewy bodies, Creutzfeldt,Jakob disease, Pick's disease and corticobasal degeneration. These studies suggest that despite the morphological and molecular diversity of brain lesions, they often exhibit a common type of spatial pattern (i.e. aggregation into clusters that are regularly distributed in the tissue). The pathogenic implications of spatial pattern analysis are discussed with reference to the individual disorders and to studies of neurodegeneration as a whole. [source] | |||||||||||||