Center for Neurosciences

Tucson, AZ, United States

Center for Neurosciences

Tucson, AZ, United States
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Ximerakis M.,Center for Neurosciences | Pampalakis G.,University of Patras | Roumeliotis T.I.,University of Southampton | Sykioti V.-S.,Center for Neurosciences | And 5 more authors.
FASEB Journal | Year: 2014

Recent evidence suggests that specific extracellular α-synuclein (α-syn) strains are implicated in the progression of Parkinson's disease (PD) pathology. It is plausible that deregulation in the normal processing of secreted α-syn may be a causative risk factor for PD. To date, the degradation mechanisms involved have received very little attention. Here, we sought to investigate factors that regulate extracellular α-syn levels. We show, for the first time, that cell-secreted α-syn forms are resistant to direct proteolysis by kallikrein-related peptidase 6 (KLK6), an extracellular enzyme known to cleave recombinant α-syn. This differential susceptibility appears to be partially due to the association of secreted α-syn with lipids. We further provide evidence that secreted α-syn can be cleaved by KLK6 indirectly through activation of a secreted metal-loprotease, suggestive of the involvement of a proteolytic cascade in the catabolism of secreted α-syn. Our results clearly suggest that physiological modifications affect the biochemical behavior of secreted α-syn and provide novel insights into mechanisms and potential targets for therapeutic interventions. © FASEB.

Knaepen K.,Vrije Universiteit Brussel | Mierau A.,German Sport University Cologne | Fernandez Tellez H.,Vrije Universiteit Brussel | Fernandez Tellez H.,Center for Neurosciences | And 3 more authors.
Neuroscience Letters | Year: 2015

To advance gait rehabilitation research it is of great importance to understand the supraspinal control of walking. In this study, the temporal and spatial characteristics of averaged electrocortical activity during treadmill walking in healthy subjects was assessed. Electroencephalography data were recorded from 32 scalp locations, averaged across trials, and related to phases of the gait cycle based on the detection of left heel strike. A characteristic temporal pattern of positive and negative potentials, similar to movement-related cortical potentials, and related to the gait cycle was observed over the cortical leg representation area. Source localization analysis revealed that mainly the primary somatosensory, somatosensory association, primary motor and cingulate cortex were activated during walking. The negative peaks of the gait-related cortical potential were associated with activity predominantly in the cingulate and prefrontal cortex, while the primary motor, primary somatosensory and somatosensory association cortex were mainly active during the positive peaks. This study identified gait-related cortical potentials during walking. The results indicate a widely distributed cortical network involved in gait control. © 2015 Elsevier Ireland Ltd.

Romano A.,University of Parma | Chibbaro S.,Lariboisere University Hospital | Marsella M.,Center for Neurosciences | Oretti G.,University of Parma | And 3 more authors.
World Neurosurgery | Year: 2010

Objectives: Sellar lesions, such as pituitary adenomas, even when extended to the suprasellar space may be usually removed through a trans-sphenoidal approach. Larger lesions extending well beyond the edges of the sellar diaphragm such as giant adenomas are best controlled with craniotomy and/or a combined approach that implies both, transphenoidal and transcranial route. Currently, the availability of more sophisticated endoscopes in this type of surgery has provided optimal angles of view and rendered the trans-sphenoidal route less invasive yet, more effective. Case Description: The authors report a case of a giant pituitary adenoma successfully managed by a simultaneous, combined endoscopic trans-sphenoidal-transventricular approach. Conclusion: In selected case of giant pituitary adenoma with ventricular extension, this technique may help to achieve a gross total removal avoiding the need of staged procedures allowing also a direct visualization of the extent of removal. Finally this approach can potentially improve gross total resection rate of different types of tumor involving this region such as cranipharyngiomas while reducing morbidity and mortality. © 2010 Elsevier Inc.

Veeramah K.R.,University of Arizona | Johnstone L.,University of Arizona | Karafet T.M.,University of Arizona | Wolf D.,University of Arizona | And 15 more authors.
Epilepsia | Year: 2013

Purpose The management of epilepsy in children is particularly challenging when seizures are resistant to antiepileptic medications, or undergo many changes in seizure type over time, or have comorbid cognitive, behavioral, or motor deficits. Despite efforts to classify such epilepsies based on clinical and electroencephalographic criteria, many children never receive a definitive etiologic diagnosis. Whole exome sequencing (WES) is proving to be a highly effective method for identifying de novo variants that cause neurologic disorders, especially those associated with abnormal brain development. Herein we explore the utility of WES for identifying candidate causal de novo variants in a cohort of children with heterogeneous sporadic epilepsies without etiologic diagnoses. Methods We performed WES (mean coverage approximately 40×) on 10 trios comprised of unaffected parents and a child with sporadic epilepsy characterized by difficult-to-control seizures and some combination of developmental delay, epileptic encephalopathy, autistic features, cognitive impairment, or motor deficits. Sequence processing and variant calling were performed using standard bioinformatics tools. A custom filtering system was used to prioritize de novo variants of possible functional significance for validation by Sanger sequencing. Key Findings In 9 of 10 probands, we identified one or more de novo variants predicted to alter protein function, for a total of 15. Four probands had de novo mutations in genes previously shown to harbor heterozygous mutations in patients with severe, early onset epilepsies (two in SCN1A, and one each in CDKL5 and EEF1A2). In three children, the de novo variants were in genes with functional roles that are plausibly relevant to epilepsy (KCNH5, CLCN4, and ARHGEF15). The variant in KCNH5 alters one of the highly conserved arginine residues of the voltage sensor of the encoded voltage-gated potassium channel. In vitro analyses using cell-based assays revealed that the CLCN4 mutation greatly impaired ion transport by the ClC-4 2Cl-/H+-exchanger and that the mutation in ARHGEF15 reduced GEF exchange activity of the gene product, Ephexin5, by about 50%. Of interest, these seven probands all presented with seizures within the first 6 months of life, and six of these have intractable seizures. Significance The finding that 7 of 10 children carried de novo mutations in genes of known or plausible clinical significance to neuronal excitability suggests that WES will be of use for the molecular genetic diagnosis of sporadic epilepsies in children, especially when seizures are of early onset and difficult to control. © 2013 Wiley Periodicals, Inc.

Espiritu M.T.,Center for Neurosciences | Rhyne A.,OrthoCarolina Spine Center | Darden II B.V.,OrthoCarolina Spine Center
Journal of the American Academy of Orthopaedic Surgeons | Year: 2010

Dural tears are among the most commonly seen complications in spine surgery. Most studies in the literature indicate that long-term outcomes are not negatively affected, provided that the tears are diagnosed early and managed appropriately. Direct suture repair remains the preferred method for the management of durotomy caused by or found during surgery. However, recent literature reports encouraging results with sutureless repair. Understanding dural anatomy, dural healing, and cerebrospinal fluid dynamics is helpful in choosing among the available management options for dural tear.

Veeramah K.R.,University of Arizona | O'Brien J.E.,University of Michigan | Meisler M.H.,University of Michigan | Cheng X.,Yale University | And 11 more authors.
American Journal of Human Genetics | Year: 2012

Individuals with severe, sporadic disorders of infantile onset represent an important class of disease for which discovery of the underlying genetic architecture is not amenable to traditional genetic analysis. Full-genome sequencing of affected individuals and their parents provides a powerful alternative strategy for gene discovery. We performed whole-genome sequencing (WGS) on a family quartet containing an affected proband and her unaffected parents and sibling. The 15-year-old female proband had a severe epileptic encephalopathy consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. We discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. This mutation alters an evolutionarily conserved residue in Nav1.6, one of the most abundant sodium channels in the brain. Analysis of the biophysical properties of the mutant channel demonstrated a dramatic increase in persistent sodium current, incomplete channel inactivation, and a depolarizing shift in the voltage dependence of steady-state fast inactivation. Current-clamp analysis in hippocampal neurons transfected with p.Asn1768Asp channels revealed increased spontaneous firing, paroxysmal-depolarizing-shift-like complexes, and an increased firing frequency, consistent with a dominant gain-of-function phenotype in the heterozygous proband. This work identifies SCN8A as the fifth sodium-channel gene to be mutated in epilepsy and demonstrates the value of WGS for the identification of pathogenic mutations causing severe, sporadic neurological disorders. © 2012 The American Society of Human Genetics.

Makiese O.,Lariboisiere Hospital Paris | Makiese O.,Paris West University Nanterre La Défense | Chibbaro S.,Lariboisiere Hospital Paris | Marsella M.,Center for Neurosciences | And 2 more authors.
Neurosurgical Review | Year: 2012

Jugular foramen paragangliomas are rare skull base tumours posing multiple complex diagnostic and management problems. We did a study to evaluate surgical technique, outcome and complications in 75 cases of tumours treated by multidisciplinary approach (i.e. combined neurosurgery, neuroradiology, ear, nose and throat surgery and intensive care unit team). Retrospective study on 75 consecutive patients with jugular foramen paragangliomas treated surgically from 1989 to 2005. Preoperative balloon occlusion test was performed in all patients as well as embolization (100%). A combined limited infratemporal and juxtacondylar approach was used in all patients. Gross total resection was achieved in 59 patients (78.7%). The most common complication was represented by lower cranial nerve deficits in five patients (6.6%), which was only temporary in three. Postoperative facial nerve weakness occurred in five cases (6.6%) and resolved in three of them. The remaining two patients underwent facial nerve reconstruction by hypoglossal/facial nerve anastomosis. Four patients (5.3%) had a postoperative cerebrospinal fluid leak, which was successfully treated by lumbar drainage. Two patients (2.7%) died because of complications related to surgical injury of lower cranial nerves: one patient developed aspiration pneumonia and septicemia and the second one developed a large cervicobulbar hematoma that led to severe respiratory distress and ultimately global cerebral hypoxia. Paragangliomas are rare and complex skull base lesions that may be managed with low morbidity and mortality if a multidisciplinary approach is considered. Facial and lower cranial nerve postoperative deficits can be limited. © Springer-Verlag 2011.

Sidtis J.J.,Nathan Kline Institute for Psychiatric Research | Tagliati M.,Cedars Sinai Medical Center | Alterman R.,Mount Sinai School of Medicine | Sidtis D.,New York University | And 2 more authors.
Journal of Cerebral Blood Flow and Metabolism | Year: 2012

Chronic, high-frequency electrical stimulation of the subthalamic nuclei (STNs) has become an effective and widely used therapy in Parkinson's disease (PD), but the therapeutic mechanism is not understood. Stimulation of the STN is believed to reorganize neurophysiological activity patterns within the basal ganglia, whereas local field effects extending to tracts adjacent to the STN are viewed as sources of nontherapeutic side effects. This study is part of a larger project investigating the effects of STN stimulation on speech and regional cerebral blood flow (CBF) in human subjects with PD. While generating measures of global CBF (gCBF) to normalize regional CBF values for a subsequent combined analysis of regional CBF and speech data, we observed a third effect of this therapy: a gCBF increase. This effect was present across three estimates of gCBF ranging from values based on the highest activity voxels to those based on all voxels. The magnitude of the gCBF increase was related to the subject's duration of PD. It is not clear whether this CBF effect has a therapeutic role, but the impact of deep brain stimulation on cerebrovascular control warrants study from neuroscience, pathophysiological, and therapeutic perspectives. © 2012 ISCBFM All rights reserved.

Pereira P.M.,University of Aveiro | Marques J.P.,University of Coimbra | Soares A.R.,University of Aveiro | Soares A.R.,Center for Neurosciences | And 2 more authors.
PLoS ONE | Year: 2010

MicroRNAs (miRNAs) are short (~22 nt) non-coding regulatory RNAs that control gene expression at the post-transcriptional level. Deregulation of miRNA expression has been discovered in a wide variety of tumours and it is now clear that they contribute to cancer development and progression. Cervical cancer is one of the most common cancers in women worldwide and there is a strong need for a non-invasive, fast and efficient method to diagnose the disease. We investigated miRNA expression profiles in cervical cancer using a microarray platform containing probes for mature miRNAs. We have evaluated miRNA expression profiles of a heterogeneous set of cervical tissues from 25 different patients. This set included 19 normal cervical tissues, 4 squamous cell carcinoma, 5 high-grade squamous intraepithelial lesion (HSIL) and 9 low-grade squamous intraepithelial lesion (LSIL) samples. We observed high variability in miRNA expression especially among normal cervical samples, which prevented us from obtaining a unique miRNA expression signature for this tumour type. However, deregulated miRNAs were identified in malignant and pre-malignant cervical tissues after tackling the high expression variability observed. We were also able to identify putative target genes of relevant candidate miRNAs. Our results show that miRNA expression shows natural variability among human samples, which complicates miRNA data profiling analysis. However, such expression noise can be filtered and does not prevent the identification of deregulated miRNAs that play a role in the malignant transformation of cervical squamous cells. Deregulated miRNAs highlight new candidate gene targets allowing for a better understanding of the molecular mechanis underlying the development of this tumour type. © 2010 Pereira et al.

PubMed | Rush University Medical Center, University of Illinois at Chicago, Gothenburg University and Center for Neurosciences
Type: Journal Article | Journal: Journal of neuroscience research | Year: 2016

Extracellular vesicles (EVs) are membrane nanovesicles of diverse sizes secreted by different cell types and are involved in intercellular communication. EVs shuttle proteins, nucleic acids, and lipids that reflect their cellular origin and could mediate their biological function in recipient cells. EVs circulate in biological fluids and are considered as potential biomarkers that could be used to analyze and characterize disease development, course and response to treatment. EVs exhibit specific distribution of glycolipids and membrane organization, but little is known about the biological significance of this distribution or how it could contribute to pathological conditions such as multiple sclerosis (MS). We provide the first description of sulfatide composition in plasma-derived EVs by ultra-high-performance liquid chromatography tandem mass spectrometry. We found that EVs of different sizes showed C16:0 sulfatide but no detectable levels of C18:0, C24:0, or C24:1 sulfatide species. Small EVs isolated at 100,000g-enriched in exosomes-from plasma of patients with MS showed a significant increase of C16:0 sulfatide compared with healthy controls. Nanoparticle tracking analysis showed that the particle size distribution in MS plasma was significantly different compared with healthy controls. Characterization of small EVs isolated from MS plasma showed similar protein content and similar levels of exosomal markers (Alix, Rab-5B) and vesicular marker MHC class I (major histocompatibility complex class I) compared with healthy controls. Our findings indicate that C16:0 sulfatide associated with small EVs is a candidate biomarker for MS that could potentially reflect pathological changes associated with this disease and/or the effects of its treatment. 2016 Wiley Periodicals, Inc.

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