Forgot your password?
New user?
New Window Opens on the Secret Life of Microbes: Scientists Develop First Microbial Profiles of Ecosystems
CAS announces the release of SciFinder Scholar for Mac OS X
Press Releases
Press Releases
| Check out our New Publishers' Select for Free Articles |
BBA - Molecular Basis of Disease (v.1802, #4)
In-vivo visualization of key molecular processes involved in Alzheimer's disease pathogenesis: Insights from neuroimaging research in humans and rodent models by Makoto Higuchi; Jun Maeda; Bin Ji; Masahiro Maruyama; Takashi Okauchi; Masaki Tokunaga; Maiko Ono; Tetsuya Suhara (pp. 373-388).
Diverse age-associated neurodegenerative disorders are featured at a molecular level by depositions of self-aggregating molecules, as represented by amyloid β peptides (Aβ) and tau proteins in Alzheimer's disease, and cascade-type chain reactions are supposedly commenced with biochemical aberrancies of these amyloidogenic components. Mutagenesis and multiplication of the genes encoding Aβ, tau and other pathogenic initiators may accelerate the incipient process at the cascade top, rationalizing generations of transgenic and knock-in animal models of these illnesses. Meanwhile, these genetic manipulations do not necessarily compress the timelines of crucial intermediate events linking amyloidogenesis and neuronal lethality, resulting in an incomplete recapitulation of the diseases. Requirements for modeling the entire cascade can be illustrated by a side-by-side comparison of humans and animal models with the aid of imaging-based biomarkers commonly applicable to different species. Notably, key components in a highly reactive state are assayable by probe-assisted neuroimaging techniques exemplified by positron emission tomography (PET), providing critical information on the in-vivo accessibility of these target molecules. In fact, multispecies PET studies in conjunction with biochemical, electrophysiological and neuropathological tests have revealed putative neurotoxic subspecies of Aβ assemblies, translocator proteins accumulating in aggressive but not neuroprotective microglia, and functionally active neuroreceptors available to endogenous neurotransmitters and exogenous agonistic ligands. Bidirectional translational studies between human cases and model strains based on this experimental paradigm are presently aimed at clarifying the tau pathogenesis, and would be expanded to analyses of disrupted calcium homeostasis and mitochondrial impairments. Since reciprocal causalities among the key processes have indicated an architectural interchangeability between cascade and network connections as an etiological representation, longitudinal imaging assays with manifold probes covering the cascade from top to bottom virtually delineate the network dynamics continuously altering in the course of the disease and its treatment, and therefore expedite the evaluation and optimization of therapeutic strategies intended for suppressing the neurodegenerative pathway over its full length.
Keywords: Dementia; Neurodegeneration; Mouse model; Positron emission tomography
Prolyl-peptidyl isomerase, Pin1, phosphorylation is compromised in association with the expression of the HFE polymorphic allele, H63D by Eric C. Hall II; Sang Y. Lee; Zachary Simmons; Elizabeth B. Neely; Wint Nandar; James R. Connor (pp. 389-395).
There is substantial interest in HFE gene variants as putative risk factors in neurodegenerative diseases such as Alzheimer disease (AD). Previous studies in cell models have shown the H63D HFE variant to result in increased cellular iron, oxidative stress, glutamate dyshomeostasis, and an increase in tau phosphorylation; all processes thought to contribute to AD pathology. Pin1 is a prolyl-peptidyl cis/ trans isomerase that can regulate the dephosphorylation of the amyloid and tau proteins. Hyperphosphorylation of these later proteins is implicated in the pathogenesis of AD and Pin1 levels are reportedly decreased in AD brains. Because of the relationship between Pin1 loss of function by oxidative stress and the increase in oxidative stress in cells with the H63D polymorphism it was logical to interrogate a relationship between Pin1 and HFE status. To test our hypothesis that H63D HFE would be associated with less Pin1 activity, we utilized stably transfected human neuroblastoma SH-SY5Y cell lines expressing the different HFE polymorphisms. Under resting conditions, total Pin1 levels were unchanged between the wild type and H63D HFE cells, yet there was a significant increase in phosphorylation of Pin1 at its serine 16 residue suggesting a loss of Pin1 activity in H63D variant cells. To evaluate whether cellular iron status could influence Pin1, we treated the WT HFE cells with exogenous iron and found that Pin1 phosphorylation increased with increasing levels of iron. Iron exposure to H63D variant cells did not impact Pin1 phosphorylation beyond that already seen suggesting a ceiling effect. Because HFE H63D cells have been shown to have more oxidative stress, the cells were treated with the antioxidant Trolox which resulted in a decrease in Pin1 phosphorylation in H63D cells with no change in WT HFE cells. In a mouse model carrying the mouse equivalent of the H63D allele, there was an increase in the phosphorylation status of Pin1 providing in vivo evidence for our findings in the cell culture model. Thus, we have shown another cellular mechanism that HFE polymorphisms influence; further supporting their role as neurodegenerative disease modifiers.
Keywords: Pin1; Iron; HFE; Oxidative stress; Phosphorylation; Neurodegenerative disease; Transgenic mice
Pathological roles of MAPK signaling pathways in human diseases by Eun Kyung Kim; Eui-Ju Choi (pp. 396-405).
The mammalian family of mitogen-activated protein kinases (MAPKs) includes extracellular signal-regulated kinase (ERK), p38, and c-Jun NH2-terminal kinase (JNK), with each MAPK signaling pathway consisting of at least three components, a MAPK kinase kinase (MAP3K), a MAPK kinase (MAP2K), and a MAPK. The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors such as oxidative stress and endoplasmic reticulum stress. These signaling pathways regulate a variety of cellular activities including proliferation, differentiation, survival, and death. Deviation from the strict control of MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Persistent activation of the JNK or p38 signaling pathways has been suggested to mediate neuronal apoptosis in AD, PD, and ALS, whereas the ERK signaling pathway plays a key role in several steps of tumorigenesis including cancer cell proliferation, migration, and invasion. In this review, we summarize recent findings on the roles of MAPK signaling pathways in human disorders, focusing on cancer and neurodegenerative diseases including AD, PD, and ALS.
Keywords: Abbreviations; MAPK; mitogen-activated protein kinase; ERK; extracellular signal-regulated kinase; JNK; c-Jun NH; 2; -terminal kinase; MAP3K; MAPK kinase kinase; MAP2K; MAPK kinase; KSR; kinase suppressor of Ras-1; MP1; MEK partner 1; JIP; JNK-interacting protein; TNF; tumor necrosis factor; IL; interleukin; MLK; mixed-lineage kinase; RTK; receptor tyrosine kinase; ASK1; apoptosis signal-regulating kinase 1; ROS; reactive oxygen species; LPS; lipopolysaccharide; ER; endoplasmic reticulum; AD; Alzheimer's disease; Aβ; amyloid-β; APP; amyloid precursor protein; PD; Parkinson's disease; LB; Lewy body; LRRK2; leucine-rich repeat kinase 2; PINK1; PTEN-induced kinase 1; MPTP; 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; iNOS; inducible NO synthase; TTRAP; TRAF- and TNF receptor-associated protein; ALS; amyotrophic lateral sclerosis; SOD1; superoxide dismutase 1; TDP-43; TAR DNA-binding protein-43; FUS; fused in sarcoma; TLS; translated in liposarcoma; FasL; Fas ligand; EGFR; epidermal growth factor receptorMAPK; JNK; p38; Neurodegenerative disease; Cancer
Lipid raft disruption protects mature neurons against amyloid oligomer toxicity by Fiorella Malchiodi-Albedi; Valentina Contrusciere; Carla Raggi; Katia Fecchi; Gabriella Rainaldi; Silvia Paradisi; Andrea Matteucci; Maria Teresa Santini; Massimo Sargiacomo; Claudio Frank; Maria Cristina Gaudiano; Marco Diociaiuti (pp. 406-415).
A specific neuronal vulnerability to amyloid protein toxicity may account for brain susceptibility to protein misfolding diseases. To investigate this issue, we compared the effects induced by oligomers from salmon calcitonin (sCTOs), a neurotoxic amyloid protein, on cells of different histogenesis: mature and immature primary hippocampal neurons, primary astrocytes, MG63 osteoblasts and NIH-3T3 fibroblasts. In mature neurons, sCTOs increased apoptosis and induced neuritic and synaptic damages similar to those caused by amyloid β oligomers. Immature neurons and the other cell types showed no cytotoxicity. sCTOs caused cytosolic Ca2+ rise in mature, but not in immature neurons and the other cell types. Comparison of plasma membrane lipid composition showed that mature neurons had the highest content in lipid rafts, suggesting a key role for them in neuronal vulnerability to sCTOs. Consistently, depletion in gangliosides protected against sCTO toxicity. We hypothesize that the high content in lipid rafts makes mature neurons especially vulnerable to amyloid proteins, as compared to other cell types; this may help explain why the brain is a target organ for amyloid-related diseases.
Keywords: Amyloid protein; Neurotoxicity; Calciton oligomer; Ganglioside; Lipid raft; Protein misfolding
The role of the autonomic nervous liver innervation in the control of energy metabolism by Chun-Xia Yi; Susanne E. la Fleur; Eric Fliers; Andries Kalsbeek (pp. 416-431).
Despite a longstanding research interest ever since the early work by Claude Bernard, the functional significance of autonomic liver innervation, either sympathetic or parasympathetic, is still ill defined. This scarcity of information not only holds for the brain control of hepatic metabolism, but also for the metabolic sensing function of the liver and the way in which this metabolic information from the liver affects the brain. Clinical information from the bedside suggests that successful human liver transplantation (implying a complete autonomic liver denervation) causes no life threatening metabolic derangements, at least in the absence of severe metabolic challenges such as hypoglycemia. However, from the benchside, data are accumulating that interference with the neuronal brain–liver connection does cause pronounced changes in liver metabolism. This review provides an extensive overview on how metabolic information is sensed by the liver, and how this information is processed via neuronal pathways to the brain. With this information the brain controls liver metabolism and that of other organs and tissues. We will pay special attention to the hypothalamic pathways involved in these liver–brain–liver circuits. At this stage, we still do not know the final destination and processing of the metabolic information that is transferred from the liver to the brain. On the other hand, in recent years, there has been a considerable increase in the understanding which brain areas are involved in the control of liver metabolism via its autonomic innervation. However, in view of the ever rising prevalence of type 2 diabetes, this potentially highly relevant knowledge is still by far too limited. Thus the autonomic innervation of the liver and its role in the control of metabolism needs our continued and devoted attention.
Keywords: Autonomic nervous system; Liver; Glucose; Hypothalamus; Neuropeptide
Hydroimidazolone modification of human αA-crystallin: Effect on the chaperone function and protein refolding ability by Mahesha H. Gangadhariah; Benlian Wang; Mikhail Linetsky; Christian Henning; Robert Spanneberg; Marcus A. Glomb; Ram H. Nagaraj (pp. 432-441).
AlphaA-crystallin is a molecular chaperone; it prevents aggregation of denaturing proteins. We have previously demonstrated that upon modification by a metabolic α-dicarbonyl compound, methylglyoxal (MGO), αA-crystallin becomes a better chaperone. AlphaA-crystallin also assists in refolding of denatured proteins. Here, we have investigated the effect of mild modification of αA-crystallin by MGO (with 20–500µM) on the chaperone function and its ability to refold denatured proteins. Under the conditions used, mildly modified protein contained mostly hydroimidazolone modifications. The modified protein exhibited an increase in chaperone function against thermal aggregation of βL- and γ-crystallins, citrate synthase (CS), malate dehydrogenase (MDH) and lactate dehydrogenase (LDH) and chemical aggregation of insulin. The ability of the protein to assist in refolding of chemically denatured βL- and γ-crystallins, MDH and LDH, and to prevent thermal inactivation of CS were unchanged after mild modification by MGO. Prior binding of catalytically inactive, thermally denatured MDH or the hydrophobic probe, 2-p-toluidonaphthalene-6-sulfonate (TNS) abolished the ability of αA-crystallin to assist in the refolding of denatured MDH. However, MGO modification of chaperone-null TNS-bound αA-crystallin resulted in partial regain of the chaperone function. Taken together, these results demonstrate that: 1) hydroimidazolone modifications are sufficient to enhance the chaperone function of αA-crystallin but such modifications do not change its ability to assist in refolding of denatured proteins, 2) the sites on the αA-crystallin responsible for the chaperone function and refolding are the same in the native αA-crystallin and 3) additional hydrophobic sites exposed upon MGO modification, which are responsible for the enhanced chaperone function, do not enhance αA-crystallin's ability to refold denatured proteins.
Keywords: Abbreviations; sHsp; small heat shock protein; DTT; dithiothreitol; GdHCl; guanidine hydrochloride; CS; citrate synthase; MDH; malate dehydrogenase; LDH; lactate dehydrogenase; MGO; methylglyoxal; NADH; β-nicotinamide adenine nucleotide reduced dipotassium salt; TNS; 2-(p-toluidinyl) naphthalene-6-sulfonic acid sodium salt; HI; hydroimidazolone; DTNB; 5,5′-Dithiobis (2-nitro-benzoic acid)AlphaA-crystallin; Chaperone; Protein modification; Methylglyoxal; Hydroimidazolone; Protein refolding