Search PubMed⌕ Search

Biomedical subjects

R S Turner

Publications and source records attributed to R S Turner.

At least 19 recordsLinked to original sources

Basal ganglia network mediates the control of movement amplitude.

In the present study we address the hypothesis that the basal ganglia are specifically involved in the planning of movement amplitude (or related covariates). This prediction has often been put forward based on the observation that Parkinson's disease (PD) patients exhibit hypokinesia. A close examination of the literature shows, however, that this commonly reported clinical symptom is not consistently echoed by experimental observations. When required to point to visual targets in the absence of vision of the moving limb, PD subjects exhibit various patterns of inaccuracy, including hypometria, hypermetria, systematic direction bias, or direction-dependent errors. They have even been shown to be as accurate as healthy, age-matched subjects. The main aim of the current study is to address the origin of these inconsistencies. To this end, we required nine patients presenting with advanced PD and 15 age-matched control subjects to perform planar reaching movements to visual targets. Eight targets were presented in equally spaced directions around a circle centered on the hand's starting location. Based on a previously validated parsing procedure, end-point errors were segmented into localization and planning errors. Localization errors refer to the existence of systematic biases in the estimation of the initial hand location. These biases can potentially transform a simple pattern of pure amplitude errors into a complex pattern involving both amplitude and direction errors. Results indicated that localization errors were different in the PD patients and the control subjects. This is not surprising knowing both that proprioception is altered in PD patients and that the ability to locate the hand at rest relies mainly on the proprioceptive sense, even when vision is available. Unlike normal subjects, localization errors in PD were idiosyncratic, lacking a consistent pattern across subjects. When the confounding effect of initial hand localization errors was canceled, we found that end-point errors were only due to the implementation of an underscaled movement gain (15%), without direction bias. Interestingly, the level of undershoot was found to increase with the severity of the disease (inferred from the Unified Parkinson's Disease Rating Scale, UPDRS, motor score). We also observed that movement variability was amplified (32%), but only along the main movement axis (extent variability). Direction variability was not significantly different in the patient population and the control group. When considered together, these results support the idea that the basal ganglia are specifically involved in the control of movement amplitude (or of some covariates). We propose that this structure participates in extent planning by modulating cortical activity and/or the tuning of the spinal interneuronal circuits.

Aged↗

X11alpha modulates secretory and endocytic trafficking and metabolism of amyloid precursor protein: mutational analysis of the YENPTY sequence.

The neuronal adaptor X11alpha interacts with the conserved -GYENPTY- sequence in the C-terminus of amyloid precursor protein (APP) or its Swedish mutation (APPswe) to inhibit Abeta40 and Abeta42 secretion. We hypothesized that the -YENP- motif essential for APP endocytosis is also essential for X11alpha-mediated effects on APP trafficking and metabolism, and that X11alpha modulates APP metabolism in both secretory and endocytic pathways. X11alpha failed to interact with the endocytic-defective APPswe mutants Y738A, N740A, or P741A, and thus did not modulate their trafficking or metabolism. However, endocytic-competent APPswe Y743A had unique trafficking and metabolism including a prolonged half-life and increased secretion of catabolites compared with APPswe. In contrast to endocytic-defective mutants, X11alpha interacted with APPswe Y743A as well as with APPswe. Thus, similar to APPswe, coexpression of X11alpha with APPswe Y743A retarded its maturation, prolonged its half-life, and inhibited APPs, Abeta40, and Abeta42 secretion. Collectively, these data suggest that by direct interaction with the APPswe -YENP- motif in the cytoplasmic tail, X11alpha modulated its trafficking and processing in both secretory and endocytic compartments, and may reduce secretion of Abeta generated in either pathway.

Adaptor Proteins, Signal Transducing↗

Spontaneous intracranial hypotension causing reversible frontotemporal dementia.

Spontaneous intracranial hypotension (SIH) causes postural headache and neurologic symptoms owing to traction and brain compression. A 66-year-old man with chronic headache and progressive personality and behavioral changes typical of frontotemporal dementia was examined. He had MRI findings of SIH with low CSF pressure. His headache, dementia, and imaging abnormalities abated after treatment with prednisone. SIH can cause reversible frontotemporal dementia, and should be considered when dementia and behavioral changes are accompanied by headache.

Aged↗

Modulation of amyloid precursor protein metabolism by X11alpha /Mint-1. A deletion analysis of protein-protein interaction domains.

Modulation of amyloid precursor protein (APP) metabolism plays a pivotal role in the pathogenesis of Alzheimer's disease. The phosphotyrosine-binding/protein interaction (PTB/PI) domain of X11alpha, a neuronal cytosolic adaptor protein, binds to the YENPTY sequence in the cytoplasmic carboxyl terminus of APP. This interaction prolongs the half-life of APP and inhibits Abeta40 and Abeta42 secretion. X11alpha/Mint-1 has multiple protein-protein interaction domains, a Munc-18 interaction domain (MID), a Cask/Lin-2 interaction domain (CID), a PTB/PI domain, and two PDZ domains. These X11alpha protein interaction domains may modulate its effect on APP processing. To test this hypothesis, we performed a deletion analysis of X11alpha effects on metabolism of APP(695) Swedish (K595N/M596L) (APP(sw)) by transient cotransfection of HEK 293 cells with: 1) X11alpha (X11alpha-wt, N-MID-CID-PTB-PDZ-PDZ-C), 2) amino-terminal deletion (X11alpha-DeltaN, PTB-PDZ-PDZ), 3) carboxyl-terminal deletion (X11alpha-DeltaPDZ, MID-CID-PTB), or 4) deletion of both termini (PTB domain only, PTB). The carboxyl terminus of X11alpha was required for stabilization of APP(sw) in cells. In contrast, the amino terminus of X11alpha was required to stimulate APPs secretion. X11alpha, X11alpha-DeltaN, and X11alpha-PTB, but not X11alpha-DeltaPDZ, were effective inhibitors of Abeta40 and Abeta42 secretion. These results suggest that additional protein interaction domains of X11alpha modulate various aspects of APP metabolism.

Adaptor Proteins, Signal Transducing↗

The pathology of REM sleep behavior disorder with comorbid Lewy body dementia.

A patient with REM sleep behavior disorder who subsequently developed probable Lewy body dementia is now reported to have a definite pathologic diagnosis of Lewy body dementia. Examination of brain revealed Lewy bodies as well as marked neuronal loss in brainstem monoaminergic nuclei-particularly locus coeruleus and substantia nigra-that inhibit cholinergic neurons in the pedunculopontine nucleus mediating atonia during REM sleep.

Aged↗

The protease inhibitor, MG132, blocks maturation of the amyloid precursor protein Swedish mutant preventing cleavage by beta-Secretase.

Amyloid (Abeta) peptides found aggregated into plaques in Alzheimer's disease are derived from the sequential cleavage of the amyloid precursor protein (APP) first by beta- and then by gamma-secretases. Peptide aldehydes, which inhibit cysteine proteases and proteasomes, reportedly block Abeta peptide secretion by interfering with gamma-secretase cleavage. Using a novel, specific, and sensitive enzyme-linked immunosorbent assay for the beta-secretase-cleaved fragment of the Swedish mutant of APP (APPSw), we determined that the peptide aldehyde, MG132, prevented beta-secretase cleavage. This block in beta-secretase cleavage was not observed with clasto-lactacystin beta-lactone and thus, cannot be attributed to proteasomal inhibition. MG132 inhibition of beta-secretase cleavage was compared with the serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF). AEBSF inhibition of beta-secretase cleavage was immediate and did not affect alpha-secretase cleavage. With MG132, inhibition was delayed and it decreased secretion of alpha-cleaved APPSw as well. Furthermore, MG132 treatment impaired maturation of full-length APPSw. Both inhibited intracellular formation of the beta-cleaved product. These results suggest that peptide aldehydes such as MG132 have multiple effects on the maturation and processing of APP. We conclude that the MG132-induced decrease in beta-secretase cleavage of APPSw is due to a block in maturation. This is sufficient to explain the previously reported peptide aldehyde-induced decrease in Abeta peptide secretion.

Amino Acid Sequence↗

Corticostriatal activity in primary motor cortex of the macaque.

Although input from corticostriatal neurons (CSNs) plays a critical role in basal ganglia functions, little is known about CSN activity during behavior. We compared the properties of antidromically identified CSNs with those of antidromically identified neurons that project via the cerebral peduncle to distant targets. Both types of neurons were recorded in primary motor cortex (M1) of two monkeys as they performed a step-tracking task in which static loads opposed or assisted simple and precued movements of the elbow or wrist. Multiple lines of evidence suggested that CSNs and corticopeduncular neurons (CPNs) belong to distinct populations. No cells were activated from both striatum and peduncle. Compared with CPNs, CSNs had slow conduction velocities and low spontaneous rates, and the activity of most was unmodulated by sensory testing or within the tasks used. CSN activity resembled that described for M1-recipient striatal neurons: perimovement firing was small in magnitude, strongly directional, and rarely showed muscle-like load effects. Contrary to a previous report, perimovement activity in most CSNs began before movement onset. CSN activity was more selective than that of CPNs: CSN sensory responses and perimovement activities were often directionally specific, CSNs were often activated exclusively by sensory stimulation, active movement, or movement preparation, and a substantial fraction of CSNs (19%) was unresponsive to any task or manipulation. Thus, CSNs transmit signals distinct from those sent to spinal cord/brainstem. The highly selective activity of CSNs suggests that a discrete (i.e., sparse) code is used to signal cortical activation states to striatum.

Action Potentials↗

What Persian Gulf War syndrome?

Recent reports of physical and neuropsychological syndromes putatively associated with service in the Persian Gulf War and ostensibly providing evidence for Gulf War Syndrome (GWS) are critically reviewed. Major methodological weaknesses are identified in the studies and it is contended that there is no solid evidence for GWS at this time. Suggestions are given for future investigations of symptoms associated with service during the Gulf War which may accurately lead to a tangible identification of a war-related illness entity.

Humans↗

Molecular analysis of the X11-mLin-2/CASK complex in brain.

A heterotrimeric complex containing Lin-10/X11alpha, Lin-2/CASK, and Lin-7 is evolutionarily conserved from worms to mammals. In Caenorhabditis elegans, it localizes Let-23, a receptor tyrosine kinase, to the basolateral side of vulval epithelium, a step crucial for proper vulva development. In mammals, the complex may also participate in receptor targeting in neurons. Accordingly, phosphotyrosine binding (PTB) and postsynaptic density-95/Discs large/Zona Occludens-1 domains found in X11alpha and mLin-2/CASK bind to cell-surface proteins, including amyloid precursor protein, neurexins, and syndecans. In this paper, we have further analyzed the X11alpha-mLin-2/CASK association that is mediated by a novel protein-protein interaction. We show that the mLin-2/CASK calmodulin kinase II (CKII) domain directly binds to a 63 amino acids peptide located between the Munc-18-1 binding site and the PTB domain in X11alpha. Ca2+/calmodulin association with mLin-2/CASK does not modify the X11alpha-mLin-2 interaction. A region containing the mLin-2/CASK guanylate kinase domain also interacts with X11alpha but with a lower affinity than the CKII domain. Immunostaining of X11alpha in the brain shows that the protein is expressed in areas shown previously to be positive for mLin-2/CASK staining. Together, our data demonstrate that the X11alpha-mLin-2 complex contacts many partners, creating a macrocomplex suitable for receptor targeting at the neuronal plasma membrane.

Adaptor Proteins, Signal Transducing↗

Role of the posterior parietal cortex in updating reaching movements to a visual target.

The exact role of posterior parietal cortex (PPC) in visually directed reaching is unknown. We propose that, by building an internal representation of instantaneous hand location, PPC computes a dynamic motor error used by motor centers to correct the ongoing trajectory. With unseen right hands, five subjects pointed to visual targets that either remained stationary or moved during saccadic eye movements. Transcranial magnetic stimulation (TMS) was applied over the left PPC during target presentation. Stimulation disrupted path corrections that normally occur in response to target jumps, but had no effect on those directed at stationary targets. Furthermore, left-hand movement corrections were not blocked, ruling out visual or oculomotor effects of stimulation.

Humans↗

Differentiated human NT2-N neurons possess a high intracellular content of myo-inositol.

myo-Inositol plays a key role in signal transduction and osmotic regulation events in the CNS. Despite the known high concentrations of inositol in the human CNS, relatively little is known about its distribution within the different cell types. In this report, inositol homeostasis was studied in NT2-N cells, a unique cell culture model of human CNS neurons. Differentiation of precursor NT2 teratocarcinoma cells into NT2-N neurons by means of retinoic acid treatment resulted in an increase in inositol concentration from 24 to 195 nmol/mg of protein. After measurement of intracellular water spaces, inositol concentrations of 1.6 and 17.4 mM were calculated for NT2 and NT2-N cells, respectively. The high concentrations of inositol in NT2-N neurons could be explained by (1) an increased uptake of inositol (3.7 vs. 1.6 nmol/mg of protein/h, for NT2-N and NT2 cells, respectively) and (2) a decreased efflux of inositol (1.7%/h for NT2-N neurons vs. 9.0%/h for NT2 cells). Activity of inositol synthase, which mediates de novo synthesis of inositol, was not detected in either cell type. The observation that CNS neurons maintain a high intracellular concentration of inositol may be relevant to the regulation of both phosphoinositide signaling and osmotic stress events in the CNS.

Antineoplastic Agents↗

Identification of an evolutionarily conserved heterotrimeric protein complex involved in protein targeting.

In Caenorhabditis elegans, lin-2, lin-7, and lin-10 genetically interact to control the trafficking of the Let-23 growth factor receptor to the basolateral surface of body epithelia. The human homologue of the lin-10 gene has recently been identified as a member of the X11 gene family. The X11 proteins contain one phosphotyrosine binding (PTB) and two PSD-95.Dlg.ZO-1 (PDZ) domains as well as an extended amino terminus. We have previously shown that the PTB domain of X11alpha (also known as Mint1) can bind to the amyloid precursor protein (APP) in a phosphotyrosine-independent fashion and can markedly inhibit the processing of APP to the amyloid beta (Abeta) peptide. Here, we report that X11alpha directly binds to the mammalian homologue of Lin-2 (mLin-2), also known as CASK. This binding is mediated by direct interaction between the Calmodulin Kinase II (CKII)-like domain of mLin-2 and the amino terminus of X11alpha. Furthermore, we can detect direct interactions between mLin-2 and mammalian Lin-7 (mLin-7). In mouse brain, we have identified a heterotrimeric complex that contains mLin-2, mLin-7, and X11alpha and that is likely important for the localization of proteins in polarized cells. This complex may play an important role in the trafficking and processing of APP in neurons.

Adaptor Proteins, Signal Transducing↗

The chaperone BiP/GRP78 binds to amyloid precursor protein and decreases Abeta40 and Abeta42 secretion.

Recent studies of cellular amyloid precursor protein (APP) metabolism demonstrate a beta-/gamma-secretase pathway resident to the endoplasmic reticulum (ER)/Golgi resulting in intracellular generation of soluble APP (APPsbeta) and Abeta42 peptide. Thus, these intracellular compartments may be key sites of amyloidogenic APP metabolism and Alzheimer's disease pathogenesis. We hypothesized that the ER chaperone immunoglobulin binding protein (BiP/GRP78) binds to and facilitates correct folding of nascent APP. Metabolic labeling and immunoprecipitation of transiently transfected human embryonic kidney 293 cells demonstrated co-precipitation of APP with GRP78, revealing their transient interaction in the ER. Maturation of cellular APP was impaired by this interaction. Furthermore, the levels of APPs, Abeta40, and Abeta42 recovered in conditioned medium were lower compared with cells transfected with APP alone. Co-expression with APP of GRP78 T37G, an ATPase mutant, almost completely blocked cellular APP maturation as well as recovery of APPs, Abeta40, and Abeta42 in conditioned medium. The inhibitory effects of GRP78 and GRP78 T37G on Abeta40 and Abeta42 secretion were magnified by co-expression with the Swedish mutation of APP (K670N/M671L). Collectively, these data suggest a transient and direct interaction of GRP78 with APP in the ER that modulates intracellular APP maturation and processing and may facilitate its correct folding.

Alzheimer Disease↗

X11 interaction with beta-amyloid precursor protein modulates its cellular stabilization and reduces amyloid beta-protein secretion.

The protein interaction domain of the neuronal protein X11 binds to the YENPTY motif within the cytoplasmic domain of beta-amyloid precursor protein (betaAPP). Amyloid-beta protein (Abeta), the major constituent of the amyloid deposited in brain of Alzheimer's disease patients, is generated by proteolytic processing of betaAPP, which occurs in part following betaAPP internalization. Because the YENPTY motif has a role in the internalization of betaAPP, the effect of X11 binding on betaAPP processing was studied in mouse neuroblastoma N2a, human embryonic kidney 293, monkey kidney COS-1, and human glial U251 cell lines transfected with wild type or mutated betaAPP cDNAs. Secretion of soluble betaAPP via alpha-secretase activity increased significantly in cells transfected with betaAPP variants containing mutations that impair interaction with X11 when compared with cells transfected with wild type cDNA. Cotransfection of betaAPP and X11 caused retention of cellular betaAPP, decreased secretion of sbetaAPPalpha, and decreased Abeta secretion. Thus, betaAPP interaction with the protein interaction domain of X11 stabilizes cellular betaAPP and thereby participates in the regulation of betaAPP processing pathways.

Adaptor Proteins, Signal Transducing↗

GABAA receptor pharmacology and subtype mRNA expression in human neuronal NT2-N cells.

Human NT2 teratocarcinoma cells differentiate into neuron-like NT2-N cells when treated with retinoic acid. GABA evoked concentration-dependent whole-cell currents in NT2-N cells with an EC50 of 21.8 microM and a Hill slope of 1.2. GABAA receptor (GABAR) currents reversed at ECl- and did not display voltage-dependent rectification. GABAR single channels opened in bursts to a 23 pS main conductance level and a 19 pS subconductance level, with infrequent openings to a 27 pS conductance level. Kinetic properties of the main conductance level were similar to other native and recombinant GABAR channels. Diazepam and zolpidem enhanced GABAR currents with moderate affinity, whereas methyl-6, 7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate inhibited GABAR currents. Loreclezole enhanced GABAR currents with high affinity, but furosemide antagonized GABAR currents with low affinity. The neurosteroids alphaxalone and pregnenolone sulfate appropriately modulated GABAR currents. Zinc blocked GABAR currents with low affinity, but lanthanum did not significantly alter NT2-N GABAR currents. Reverse transcription PCR (RT-PCR) performed on RNA from NT2-N cells clearly detected transcripts encoding human alpha2, alpha3, alpha5, beta3, gamma3, and pi subtypes. The combined pharmacological and RT-PCR results are most consistent with a single or predominant GABAR isoform composed of an alpha2 and/or alpha3 subtype combined with the beta3 and gamma3 subtypes. The data do not rule out receptors containing combinations of alpha2 and/or alpha3 subtypes with the alpha5 subtype or receptors with both beta1 and beta3 subtypes. The presence or absence or the pi subunit in functionally expressed receptors could not be determined.

Anticonvulsants↗

The X11alpha protein slows cellular amyloid precursor protein processing and reduces Abeta40 and Abeta42 secretion.

Constitutive amyloid precursor protein (APP) metabolism results in the generation of soluble APP (APPs) and Abeta peptides, including Abeta40 and Abeta42-the major component of amyloid plaques in Alzheimer's disease brain. The phosphotyrosine binding (PTB) domain of X11 binds to a peptide containing a YENPTY motif found in the carboxyl terminus of APP. We have cloned the full-length X11 gene now referred to as X11alpha. Coexpression of X11alpha with APP results in comparatively greater levels of cellular APP and less APPs, Abeta40, and Abeta42 recovered in conditioned medium of transiently transfected HEK 293 cells. These effects are impaired by a single missense mutation of either APP (Y682G within the YENPTY motif) or X11alpha (F608V within the PTB domain), which diminishes their interaction, thus demonstrating specificity. The inhibitory effect of X11alpha on Abeta40 and Abeta42 secretion is amplified by coexpression with the Swedish mutation of APP (K595N/M596L), which promotes its amyloidogenic processing. Pulse-chase analysis demonstrates that X11alpha prolongs the half-life of APP from approximately 2 h to approximately 4 h. The effects of X11alpha on cellular APP and APPs recovery were confirmed in a 293 cell line stably transfected with APP. The specific binding of the PTB domain of X11alpha to the YENPTY motif-containing peptide of APP appears to slow cellular APP processing and thus reduces recovery of its soluble fragments APPs, Abeta40, and Abeta42 in conditioned medium of transfected HEK 293 cells. X11alpha may be involved in APP trafficking and metabolism in neurons and thus may be implicated in amyloidogenesis in normal aging and Alzheimer's disease brain.

Alzheimer Disease↗

Motor subcircuits mediating the control of movement velocity: a PET study.

The influence of changes in the mean velocity of movement on regional cerebral blood flow (rCBF) was studied using positron emission tomography (PET) in nine healthy right-handed adults while they performed a smooth pursuit visuomanual tracking task. Images of relative rCBF were obtained while subjects moved a hand-held joystick to track the movement of a target at three different rates of a sinusoidal displacement (0.1, 0.4, and 0.7 Hz). Significant changes in rCBF between task conditions were detected using analysis of variance and weighted linear contrasts. The kinematics of arm and eye movements indicated that subjects performed tasks in a similar manner, particularly during the faster two tracking conditions. Significant increases in rCBF during arm movement (relative to an eye tracking only control condition) were detected in a widespread network of areas known for their involvement in motor control. The activated areas included primary sensorimotor (M1S1), dorsal and mesial premotor, and dorsal parietal cortices in the left hemisphere and to a lesser extent the sensorimotor and superior parietal cortices in the right hemisphere. Subcortically, activations were found in the left putamen, globus pallidus (GP), and thalamus, in the right basal ganglia, and in the right anterior cerebellum. Within the cerebral volume activated with movement, three areas had changes in rCBF that correlated positively with the rate of movement: left M1S1, left GP, and right anterior cerebellum. No movement-related sites had rCBF that correlated negatively with the rate of movement. Regressions of mean percent change (MPC) in rCBF onto mean hand velocity yielded two nonoverlapping subpopulations of movement-related loci, the three sites with significant rate effects and regression slopes steeper than 0.17 MPC.cm-1.s-1 and all other sites with nonsignificant rate effects and regression slopes below 0.1 MPC.cm-1. s-1. Moreover, the effects of movement per se and of movement velocity varied in magnitude independently. These results confirm previous reports that movement-related activations of M1S1 and cerebellum are sensitive to movement frequency or some covarying parameter of movement. The activation of GP with increasing movement velocity, not described in previous functional-imaging studies, supports the hypothesis that the basal ganglia motor circuit may be involved preferentially in controlling or monitoring the scale and/or dynamics of arm movements. The remaining areas that were activated equally for all movement rates may be involved in controlling higher level aspects of motor control that are independent of movement dynamics.

Aged↗