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Results for “Protein Aggregation, Pathological”

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PubMed1999

Pseudolymphomatous folliculitis: a clinicopathologic study of 15 cases of cutaneous pseudolymphoma with follicular invasion.

We report the clinical, histopathologic, and immunohistologic features of 15 cases of pseudolymphomatous folliculitis (PLF). The patients comprised seven males and eight females (mean age, 38.6 years; age range, 2-67 years). All patients had dome-shaped or flat-elevated nodules suggestive of cutaneous lymphoid hyperplasias (CLHs). The lesions were solitary in all 15 cases, except in one case with duplex lesions. All lesions were located on the face and measured less than 1.5 cm. In 14 cases with one lesion each, five lesions showed rapid regression after incisional biopsy, whereas the remaining nine underwent excisional biopsy. In the case with duplex lesions, one regressed spontaneously after excisional biopsy of the other. Histopathologically, all PLFs showed dense lymphocytic infiltrates from the dermis to the subcutis simulating cutaneous lymphomas. The walls of hair follicles in all cases were enlarged and irregularly deformed with their epithelium blurred by lymphocytic infiltrates; we called this change "activation" of hair follicles. In nine cases, many atypical lymphocytes were intermingled; three of these cases had been misdiagnosed as cutaneous T-cell lymphoma at other institutions. Immunohistologically, 10 and 5 cases showed predominantly B cells and predominantly T cells, respectively. Remarkably, all lesions showed increased numbers of perifollicular histiocytes expressing anti-S-100 protein and CD1a, and seven lesions showed histiocytes in aggregates. We conclude that PLF is a subset of CLH with characteristic clinical and pathologic features showing perifollicular clustering of T-cell-associated dendritic cells with activation of pilosebaceous units. PLF is an entity to be differentiated from malignant lymphomas and other cutaneous pseudolymphomas.

Adolescent↗

PubMed2006

Signaling from MARK to tau: regulation, cytoskeletal crosstalk, and pathological phosphorylation.

The hyperphosphorylation of tau is an early step in the degeneration of neurons in Alzheimer's disease and other tauopathies. Of particular importance is the phosphorylation of tau in the repeat domain which detaches tau from microtubules. This makes microtubules dynamic for their role in differentiation and neurite outgrowth, and it controls the level of tau on the microtubule surface which keeps the tracks clear for axonal transport. However, the detachment of tau from microtubules can also initiate the reactions that lead to pathological aggregation into neurofibrillary tangles. Phosphorylation of tau in the repeat domain is achieved by the kinase MARK/Par-1, a member of the calcium/calmodulin-dependent protein kinase group of kinases. In this report, we focus on the modes of MARK regulation. MARK contains several domains which offer multiple ways of regulation by posttranslational modification (e.g. phosphorylation), interactions with scaffolding proteins and subcellular targeting (e.g. 14-3-3), and interactions with other proteins. We consider in particular the interactions between MARK and other kinases, notably MARKK/TAO-1 and PAK5. MARKK (a member of the Ste20 family of kinases) activates MARK by phosphorylating it at a critical threonine residue within the activation loop. Activated MARK in turn phosphorylates tau, causes its detachment from microtubules and renders them labile. PAK5 inactivates MARK, not by phosphorylation, but by binding to the catalytic domain. PAK5 contributes to microtubule stability by preventing the MARK-induced phosphorylation of tau; conversely, PAK5 contributes to actin dynamics, presumably through the activation of cofilin, an F-actin severing protein. Thus, MARK and its regulators MARKK and PAK5 appear to mediate the crosstalk between the actin and microtubule cytoskeleton in an antagonistic fashion.

Animals↗

PubMed2003

Update on Parkinson disease.

This Update reviews developments in the pathophysiology and treatment of Parkinson disease during the past several years. In the area of pathophysiology, studies have addressed the contribution of environmental factors such as caffeine and pesticides. Large-scale epidemiologic studies have also expanded the role genetic factors are thought to play. Detailed studies of kindreds with familial Parkinson disease due to alpha-synuclein and parkin have catalyzed basic science investigations into the pathologic mechanisms of the disease. These studies have led to the development of a pathophysiologic model of Parkinson disease that emphasizes abnormal protein aggregation. Studies of treatment have clarified the relative roles of l-dopa and dopamine agonists in early Parkinson disease and shown the potential for surgical interventions, particularly deep-brain stimulation, to relieve the symptoms of advanced, medically refractory disease.

Antiparkinson Agents↗

PubMed2006

It may take inflammation, phosphorylation and ubiquitination to 'tangle' in Alzheimer's disease.

Neurofibrillary tangles (NFT) are one of the pathologic hallmarks of Alzheimer's disease (AD). Their major component is tau, a protein that becomes hyperphosphorylated and accumulates into insoluble paired helical filaments. During the course of the disease such filaments aggregate into bulky NFT that get ubiquitinated. What triggers their formation is not known, but neuroinflammation could play a role. Neuroinflammation is an active process detectable in the earliest stages of AD. The neuronal toxicity associated with inflammation makes it a potential risk factor in the pathogenesis of chronic neurodegenerative diseases, such as AD. Determining the sequence of events that lead to this devastating disease has become one of the most important goals for AD prevention and treatment. In this review we focus on three topics relevant to AD pathology and to NFT formation: (1) what triggers CNS inflammation resulting in glia activation and neuronal toxicity; (2) how products of inflammation might change the substrate specificity of kinases/phosphatases leading to tau phosphorylation at pathological sites; (3) the relationship between the ubiquitin/proteasome pathway and tau ubiquitination and accumulation in NFT. The overall aim of this review is to provide a challenging and sometimes provocative survey of important contributions supporting the view that CNS inflammation might be a critical contributor to AD pathology. Neuronal cell death resulting from neuroinflammatory processes may have devastating effects as, in the vast majority of cases, neurons lost to disease cannot be replaced. In order to design therapies that will prevent endangered neurons from dying, it is critical that we learn more about the effects of neuroinflammation and its products.

Alzheimer Disease↗

PubMed1999

cAMP-dependent protein kinase phosphorylations on tau in Alzheimer's disease.

To elucidate the role cAMP-dependent protein kinase (PKA) phosphorylations on tau play in Alzheimer's disease, we have generated highly specific monoclonal antibodies, CP-3 and PG-5, which recognize the PKA-dependent phosphorylations of ser214 and ser409 in tau respectively. The present study demonstrates by immunohistochemical analysis, CP-3 and PG-5 immunoreactivity with neurofibrillary pathology in both early and advanced Alzheimer's disease, but not in normal brain tissue and demonstrates that cAMP-dependent protein kinase phosphorylations on tau precede or are coincident with the initial appearance of filamentous aggregates of tau. Studies using heat-stable preparations demonstrate that neither site appears to be phosphorylated to any appreciable extent in normal rodent or human brain. Further analysis demonstrates that the beta catalytic subunit of PKA (Cbeta), the beta II regulatory subunit of PKA (RIIbeta), and the 79 kDa A-kinase-anchoring-protein (AKAP79), are tightly associated with the neurofibrillary pathology, positioning cAMP-dependent protein kinase to participate directly in the pathological hyperphosphorylation of tau seen in Alzheimer's disease.

Alzheimer Disease↗

PubMed2002

Inhibition of human surfactant protein A function by oxidation intermediates of nitrite.

NitraNitration of protein tyrosine residues by peroxynitrite (ONOO - ) has been implicated in a variety of inflammatory diseases such as acute respiratory distress syndrome (ARDS). Pulmonary surfactant protein A (SP-A) has multiple functions including host defense. We report here that a mixture of hypochlorous acid (HOCl) and nitrite (NO 2 - ) induces nitration, oxidation, and chlorination of tyrosine residues in human SP-A and inhibits SP-A's ability to aggregate lipids and bind mannose. Nitration and oxidation of SP-A was not altered by the presence of lipids, suggesting that proteins are preferred targets in lipid-rich mixtures such as pulmonary surfactant. Moreover, both horseradish peroxidase and myeloperoxidase (MPO) can utilize NO 2 - and hydrogen peroxide (H 2 O 2 ) as substrates to catalyze tyrosine nitration in SP-A and inhibit its lipid aggregation function. SP-A nitration and oxidation by MPO is markedly enhanced in the presence of physiological concentrations of Cl - and the lipid aggregation function of SP-A is completely abolished. Collectively, our results suggest that MPO released by activated neutrophils during inflammation utilizes physiological or pathological levels of NO 2 - to nitrate proteins, and may provide an additional mechanism in addition to ONOO - formation, for tissue injury in ARDS and other inflammatory diseases associated with upregulated *NO and oxidant production.

Bronchoalveolar Lavage Fluid↗

PubMed2004

Inhibition of amyloid fibrillogenesis and toxicity by a peptide chaperone.

Aggregation of proteins in tissues is associated with several diseases, including Alzheimer's disease. It is characterized by the accumulation of amyloid beta peptide (Abeta) in the extracellular spaces of the brain cells, resulting in neuronal death and other pathological changes. alpha-Crystallin, a small heat-shock protein in lens, and a peptide chaperone having the functional site sequence DFVIFLDVKHFSPEDLTVK of alphaA-crystallin may inhibit Abeta fibrillogenesis and toxicity. The peptide chaperone (mini-alphaA-crystallin), having an Abeta interacting domain and a complex solubilizing domain, was shown in previous studies to prevent aggregation of several proteins under denaturing conditions. In this in vitro study, using transmission electron microscopy and thioflavin T binding assay, we show that mini-alphaA-crystallin arrests the fibril formation of Abeta peptides. Mini-alphaA-crystallin also suppresses the toxic action of Abeta on rat pheochromocytoma (PC 12) cells. The wide chaperoning capability of the peptide and its ability to inhibit amyloid fibril formation and suppress toxicity suggest that mini-alphaA-crystallin may serve as a universal chaperone in controlling diseases of protein aggregation, including Alzheimer's disease.

Alzheimer Disease↗

PubMed2006

The application of HSP70 as a target for gene therapy.

The 70-kDa heat shock proteins (HSP70s) are well-studied and characterized heat shock proteins (HSPs). They constitute essential components of a quality control system of protein synthesis, and function as molecular chaperones to prevent proteins from misfolding and aggregating during both de novo synthesis and under conditions of stress. Moreover, it is now well established that HSP70s play important cytoprotective roles in various pathological settings. Recognition of molecular chaperone and cytoprotective functions of HSP70s is fostering active investigations into the potential of HSP70s as therapeutic targets at the laboratory level. Gaining insight into these recent advances may have profound implications in the development of HSP70-based clinical studies.

Adenosine Triphosphatases↗

PubMed2001

Recent advances in the understanding of the role of synaptic proteins in Alzheimer's Disease and other neurodegenerative disorders.

Synaptic damage is an early pathological event common to many neurodegenerative disorders such as Alzheimer's disease (AD) and is the best correlate to the cognitive impairment. Several molecules involved in AD and in other neurodegenerative disorders play an important role in synaptic function and when misfolded aggregate and form amyloid fibrils. Synaptic proteins with an amyloid domain include amyloid beta-protein precursor, prion protein, huntingtin, ataxin-1 and alpha-synuclein. Two of the possible mechanisms by which alterations in synaptic proteins lead to synapse damage are: 1) misfolded or aggregated synaptic molecules have lost their normal function and/or 2) they have gained a toxic capacity. Recent studies support the possibility that while oligomers are toxic, polymers might be inactive. The mechanisms by which oligomers trigger synapse loss could be related to their ability to triggers stress signals once they enter the nucleus and/or accumulate at the endoplasmic reticulum.

Journal Article↗

PubMed2001

Glial cell death induced by overexpression of alpha-synuclein.

alpha-Synuclein is present in intracellular protein aggregates that are hallmarks of common neurodegenerative disorders including Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. alpha-Synuclein is localized in neurons and presynaptic terminals. Under pathological conditions, however, it is also found in glia. The role of alpha-synuclein in glial cells and its relevance to the molecular pathology of neurodegenerative diseases is presently unclear. To investigate the consequence of alpha-synuclein overexpression in glia, we transfected U373 astrocytoma cells with vectors encoding wild-type human alpha-synuclein or C-terminally truncated synuclein fused to red fluorescent protein. alpha-synuclein immunocytochemistry of transfected astroglial cells revealed diffuse cytoplasmic labeling associated with discrete inclusions both within cell bodies and processes. Susceptibility to oxidative stress was increased in astroglial cells overexpressing alpha-synuclein, particularly in the presence of cytoplasmic inclusions. Furthermore, overexpression of alpha-synuclein induced apoptotic death of astroglial cells as shown by TUNEL staining. Our in vitro model is the first to replicate salient features of the glial pathology associated with alpha-synucleinopathies. It provides a simple testbed to further explore the cascade of events that leads to apoptotic glial cell death in some of these disorders; it may also be useful to assess the effects of therapeutic interventions including antioxidative and antiapoptotic strategies.

Apoptosis↗

PubMed2003

Histone H3 is aberrantly phosphorylated in glutamine-repeat diseases.

Double-labeling immunohistochemical studies staining with anti-ubiquitin and anti-phosphoserine antibodies and application of an enzymatic dephosphorylation technique reveal neuronal inclusions and affected nuclei to be aberrantly phosphorylated in brain tissues with patients with glutamine-repeat diseases. Regional distribution of the phosphorylated nuclei in neurons correlates with the pathology. To identify the target nuclear protein, transient expression of Huntington's disease exon 1 gene containing an expanded glutamine repeat was generated in a cell culture and nuclear inclusions were isolated with a fluorescence-activated cell sorting system. Immunoblotting studies of the aggregated nuclear proteins using anti-phosphoserine antibody demonstrate the protein of the aberrant phosphorylation as histone H3. The immunoblots of control and diseased brain tissues demonstrate that the phosphorylation of histone H3 is commonly increased in the diseased brains. Aberrant phosphorylation of histone H3 is surmised to be a shared pathological process in glutamine-repeat diseases.

Adult↗

PubMed2006

Effect of acetylcholinesterase inhibitors on AChE-induced PrP106-126 aggregation.

Transmissible spongiform encephalopaties are caused by an extracellular surface protein, the scrapie prion protein (PrPsc), which is an aberrant form of normal and functional cellular PrP (PrPc). The pathological hallmarks of these diseases are the accumulation and deposition of PrPsc in the form of amyloid fibrils in the central nervous system (Tateishi et al., 1988), similar to amyloid-beta (Abeta) protein in Alzheimer's disease (AD). In some patients, Abeta and prion pathology can coexist (Hainfellner et al., 1998), and a common spatial pattern of protein deposition has been described (Armstrong et al., 2001). In addition, it is well-known that acetylcholinesterase (AChE) colocalizes with Abeta deposits of brains in AD patients and accelerates assembly of Abeta peptides through the peripheral site of the enzyme (Inestrosa et al., 1996). The aim of the present study was to analyze time course and concentration dependence of the AChE proaggregating effect on synthetic peptide-spanning residues 106-126 of human PrP (PrP106-126) and the reversion of this effect by different AChE inhibitors (AChEIs).

Acetylcholinesterase↗

PubMed2006

Expansion of amino acid homo-sequences in proteins: insights into the role of amino acid homo-polymers and of the protein context in aggregation.

Expansion of amino acid homo-sequences, such as polyglutamines or polyalanines, in proteins has been directly implicated in various degenerative diseases through a mechanism of protein misfolding and aggregation. However, it is still unclear how the nature of the expansion and the protein context influence the tendency of a protein to aggregate. Here, we have addressed these questions using spinocerebellar ataxia type-3 (ATX3) protein, the best characterised of the polyglutamine proteins, chosen as a model system. Using a transfected mammalian cell line, we demonstrate that ATX3 aggregation is noticeably reduced by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture and of the amino acid homo-sequence on pathology.

Amino Acids↗

PubMed2004

Astrocytic regulation of NMDA receptor subunit composition modulates the toxicity of prion peptide PrP106-126.

Prion diseases are neurodegenerative conditions. The main pathological alterations common to these diseases include the loss of neurones, gliosis and the deposition of an abnormal isoform of the prion protein in aggregates in the nervous tissue. Prevention of the devastating effects of prion disease requires prevention of neuronal death. Therefore, understanding the mechanism by which this occurs is essential. Cell culture studies using the synthetic peptide PrP106-126 have been central to developing a model of this mechanism. Using a coculture system, we have shown that PrP106-126 caused neuronal death mediated by glutamate. This neuronal death resulted from modification of the expression of NMDA receptor subtypes stimulated by the exposure of neurones to the combination of astrocytic factors, elevated Cu and PrP106-126. The results of these experiments suggest neuronal death in prion disease might be reduced by the use of NMDA receptor antagonists such as MK801 or inhibitors of the arachidonic acid metabolism pathway.

Animals↗

PubMed2000

Mice transgenic for the human Huntington's disease mutation have reduced sensitivity to kainic acid toxicity.

The mechanism underlying the pathology of Huntington's disease (HD) is unknown, although there is substantial evidence supporting a role for excitotoxicity. The discovery of abnormal aggregations of protein in the brains of patients with HD, as well as in the brains of transgenic mice modeling this disease, has led to the suggestion that these "inclusions" have a pathogenic role. However, the relationship between inclusion formation and the progressive neurodegeneration in HD remains unclear. Here, we used mice transgenic for the first exon of the HD gene and an expanded CAG repeat (R6/2 line) to examine the role of neuronal intranuclear inclusions in kainic acid (KA) excitotoxicity. Unexpectedly, we found that the toxicity of KA was markedly attenuated in R6/2 mice compared with wild-type mice. In particular, the number and severity of KA-induced seizures in R6/2 mice was significantly reduced. When seizures occurred in 3-week-old R6/2 mice, we found lesions in the CA3 region of the hippocampus. However, neuronal intranuclear inclusions were not induced by KA in 3-week-old mice. Further, in older mice (9 weeks), the pre-existence of inclusions in CA3 neurons did not increase the vulnerability of neurons to KA, since no lesions were seen in 9-week R6/2 mouse brain. Our results suggest that an increased susceptibility to excitotoxic stimuli does not underlie the early phase of the neurological phenotype in R6/2 mice, although a role in later stages is not excluded by our findings. The significance of these findings is discussed in the context of the R6/2 mouse as a model for HD.

Animals↗

PubMed1999

Designing conditions for in vitro formation of amyloid protofilaments and fibrils.

We have been able to convert a small alpha/beta protein, acylphosphatase, from its soluble and native form into insoluble amyloid fibrils of the type observed in a range of pathological conditions. This was achieved by allowing slow growth in a solution containing moderate concentrations of trifluoroethanol. When analyzed with electron microscopy, the protein aggregate present in the sample after long incubation times consisted of extended, unbranched filaments of 30-50 A in width that assemble subsequently into higher order structures. This fibrillar material possesses extensive beta-sheet structure as revealed by far-UV CD and IR spectroscopy. Furthermore, the fibrils exhibit Congo red birefringence, increased fluorescence with thioflavine T and cause a red-shift of the Congo red absorption spectrum. All of these characteristics are typical of amyloid fibrils. The results indicate that formation of amyloid occurs when the native fold of a protein is destabilized under conditions in which noncovalent interactions, and in particular hydrogen bonding, within the polypeptide chain remain favorable. We suggest that amyloid formation is not restricted to a small number of protein sequences but is a property common to many, if not all, natural polypeptide chains under appropriate conditions.

Acid Anhydride Hydrolases↗

PubMed1999

Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology.

Huntington's disease is a progressive neurodegenerative disorder caused by a polyglutamine [poly(Q)] repeat expansion in the first exon of the huntingtin protein. Previously, we showed that N-terminal huntingtin peptides with poly(Q) tracts in the pathological range (51-122 glutamines), but not with poly(Q) tracts in the normal range (20 and 30 glutamines), form high molecular weight protein aggregates with a fibrillar or ribbon-like morphology, reminiscent of scrapie prion rods and beta-amyloid fibrils in Alzheimer's disease. Here we report that the formation of amyloid-like huntingtin aggregates in vitro not only depends on poly(Q) repeat length but also critically depends on protein concentration and time. Furthermore, the in vitro aggregation of huntingtin can be seeded by preformed fibrils. Together, these results suggest that amyloid fibrillogenesis in Huntington's disease, like in Alzheimer's disease, is a nucleation-dependent polymerization.

Amino Acid Sequence↗

PubMed2006

Prostaglandin J2 alters pro-survival and pro-death gene expression patterns and 26 S proteasome assembly in human neuroblastoma cells.

Many neurodegenerative disorders are characterized by two pathological hallmarks: progressive loss of neurons and occurrence of inclusion bodies containing ubiquitinated proteins. Inflammation may be critical to neurodegeneration associated with ubiquitin-protein aggregates. We previously showed that prostaglandin J2 (PGJ2), one of the endogenous products of inflammation, induces neuronal death and the accumulation of ubiquitinated proteins into distinct aggregates. We now report that temporal microarray analysis of human neuroblastoma SK-N-SH revealed that PGJ2 triggered a "repair" response including increased expression of heat shock, protein folding, stress response, detoxification and cysteine metabolism genes. PGJ2 also decreased expression of cell growth/maintenance genes and increased expression of apoptotic genes. Over time pro-death responses prevailed over pro-survival responses, leading to cellular demise. Furthermore, PGJ2 increased the expression of proteasome and other ubiquitin-proteasome pathway genes. This increase failed to overcome PGJ2 inhibition of 26 S proteasome activity. Ubiquitinated proteins are degraded by the 26 S proteasome, shown here to be the most active proteasomal form in SK-N-SH cells. We demonstrate that PGJ2 impairs 26 S proteasome assembly, which is an ATP-dependent process. PGJ2 perturbs mitochondrial function, which could be critical to the observed 26 S proteasome disassembly, suggesting a cross-talk between mitochondrial and proteasomal impairment. In conclusion neurotoxic products of inflammation, such as PGJ2, may play a role in neurodegenerative disorders associated with the aggregation of ubiquitinated proteins by impairing 26 S proteasome activity and inducing a chain of events that culminates in neuronal cell death. Temporal characterization of these events is relevant to understanding the underlying mechanisms and to identifying potential early biomarkers.

Biomarkers↗