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Search Results for all work with filters:

  • Biology, Neuroscience
  • neurosci
  • mutat

Work 1-10 of 29

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Article

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

by Marc Remke; Vijay Ramaswamy; John Peacock; David J. H. Shih; Christian Koelsche; Paul A. Northcott; Nadia Hill; Florence M. G. Cavalli; Marcel Kool; Xin Wang; Stephen C. Mack; Mark Barszczyk; A. Sorana Morrissy; Xiaochong Wu; Sameer Agnihotri; Betty Luu ; David T.W. Jones; Livia Garzia; Adrian M. Dubuc; Nataliya Zhukova; Robert Vanner; Johan M. Kros; Pim J. French; Erwin Van Meir; Rajeev Vibhakar; Karel Zitterbart; Jennifer A. Chan; Laszlo Bognar; Almos Klekner; Boleslaw Lach ; Shin Jung; Ali G. Saad; Linda M. Liau; Steffen Albrecht; Massimo Zollo; Michael Cooper; Reid C. Thompson; Oliver O. Delattre; Franck Bourdeaut; Francois F. Doz; Miklos Garami; Peter Hauser; Carlos G. Carlotti; Timothy E. Van Meter; Luca Massimi; Daniel Fults; Scott L. Pomeroy; Toshiro Kumabe ; Young Shin Ra; Jeffrey R. Leonard; Samer K. Elbabaa; Jaume Mora; Joshua B. Rubin; Yoon-Jae Cho; Roger E. McLendon; Darrell D. Bigner; Charles G. Eberhart; Maryam Fouladi; Robert J. Wechsler-Reya; Claudia C. Faria; Sidney E. Croul; Annie Huang ; Eric Bouffet; Cynthia E. Hawkins ; Peter B. Dirks; William A. Weiss ; Ulrich Schuller; Ian F. Pollack; Stefan Rutkowski; David Meyronet; Anne Jouvet; Michelle Fevre-Montange; Nada Jabado; Marta Perek-Polnik; Wieslawa A. Grajkowska; Seung-Ki Kim; James T. Rutka ; David Malkin; Uri Tabori; Stefan M. Pfister; Andrey Korshunov; Andreas von Deimling

2013

Subjects
  • Biology, Neuroscience
  • Health Sciences, Pathology
  • File Download
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Abstract:Close

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in < 5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Article

A Rare Variant Identified Within the GluN2B C-Terminus in a Patient with Autism Affects NMDA Receptor Surface Expression and Spine Density

by Shuxi Liu; Liang Zhou; Hongjie Yuan; Marta Vieira; Antonio Sanz-Clemente; John D. Badger; Wei Lu; Stephen Traynelis; Katherine W. Roche

2017

Subjects
  • Biology, Neuroscience
  • Health Sciences, Pharmacology
  • Biology, Genetics
  • File Download
  • View Abstract

Abstract:Close

NMDA receptors (NMDARs) are ionotropic glutamate receptors that are crucial for neuronal development and higher cognitive processes. NMDAR dysfunction is involved in a variety of neurological and psychiatric diseases; however, the mechanistic link between the human pathology and NMDAR dysfunction is poorly understood. Rare missense variants within NMDAR subunits have been identified in numerous patients with mental or neurological disorders. We specifically focused on the GluN2B NMDAR subunit, which is highly expressed in the hippocampus and cortex throughout development. We analyzed several variants located in the GluN2B C terminus and found that three variants in patients with autism (S1415L) or schizophrenia (L1424F and S1452F) (S1413L, L1422F, and S1450F in rodents, respectively) displayed impaired binding to membrane-associated guanylate kinase (MAGUK) proteins. In addition, we observed a deficit in surface expression for GluN2B S1413L. Furthermore, there were fewer dendritic spines in GluN2B S1413L-expressing neurons. Importantly, synaptic NMDAR currents in neurons transfected with GluN2B S1413L in GluN2A/B-deficient mouse brain slices revealed only partial rescue of synaptic current amplitude. Functional properties of GluN2B S1413L in recombinant systems revealed no change in receptor properties, consistent with synaptic defects being the result of reduced trafficking and targeting of GluN2B S1413L to the synapse. Therefore, we find that GluN2B S1413L displays deficits in NMDAR trafficking, synaptic currents, and spine density, raising the possibility that this mutationmaycontribute to the phenotype in this autism patient.Morebroadly, our research demonstrates that the targeted study of certain residues in NMDARs based on rare variants identified in patients is a powerful approach to studying receptor function.

Article

Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer's Disease Dementia in Individuals With Mild Cognitive Impairment

by Yong Shen; Haibo Wang; Qiying Sun; Hailan Yao; Andrew P Keegan; Mike Mullan; Jeffrey Wilson; Simone Lista; Thomas Leyhe; Christoph Laske; Dan Rujescu; Allan Levey; Anders Wallin; Kaj Blennow; Rena Li; Harald Hampel

2018

Subjects
  • Biology, Neuroscience
  • Biology, Physiology
  • Psychology, Cognitive
  • File Download
  • View Abstract

Abstract:Close

Background: Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer's disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects. Methods: Seventy-five patients with probable AD, 96 individuals with MCI, and 53 age-matched and sex-matched healthy control subjects were recruited from three independent international academic memory clinics and AD research expert centers. Plasma BACE1 activity was measured by a synthetic fluorescence substrate enzyme-linked immunosorbent assay. BACE1 protein expression was assessed by Western blotting using three different antibodies that recognize the epitopes of the N-terminus, C-terminus, and full-length BACE1. Results: Compared with healthy control subjects, plasma BACE1 activity (V max ) significantly increased by 53.2% in subjects with MCI and by 68.9% in patients with probable AD. Subjects with MCI who converted to probable AD dementia at follow-up examinations exhibited significantly higher BACE1 activity compared with cognitively stable MCI nonconverters and showed higher levels of BACE1 activity than patients with AD. Conclusions: Plasma BACE1 activity is significantly increased in MCI converters and patients with probable AD. The sensitivities and specificities of BACE1 activity for the patients were 84% and 88%, respectively. Our results indicate that plasma BACE1 activity may be a biomarker for AD risk and could predict progression from prodromal to probable AD dementia.

Article

Cochlear Gene Therapy for Sensorineural Hearing Loss: Current Status and Major Remaining Hurdles for Translational Success

by Wenjuan Zhang; Sun Myoung Kim; Wenwen Wang; Cuiyuan Cai; Yong Feng; Weijia Kong; Xi Erick Lin

2018

Subjects
  • Health Sciences, Medicine and Surgery
  • Biology, Neuroscience
  • File Download
  • View Abstract

Abstract:Close

Sensorineural hearing loss (SNHL) affects millions of people. Genetic mutations play a large and direct role in both congenital and late-onset cases of SNHL (e.g., age-dependent hearing loss, ADHL). Although hearing aids can help moderate to severe hearing loss the only effective treatment for deaf patients is the cochlear implant (CI). Gene- and cell-based therapies potentially may preserve or restore hearing with more natural sound perception, since their theoretical frequency resolution power is much higher than that of cochlear implants. These biologically-based interventions also carry the potential to re-establish hearing without the need for implanting any prosthetic device; the convenience and lower financial burden afforded by such biologically-based interventions could potentially benefit far more SNHL patients. Recently major progress has been achieved in preclinical studies of cochlear gene therapy. This review critically evaluates recent advances in the preclinical trials of gene therapies for SNHL and the major remaining challenges for the development and eventual clinical translation of this novel therapy. The cochlea bears many similarities to the eye for translational studies of gene therapies. Experience gained in ocular gene therapy trials, many of which have advanced to clinical phase III, may provide valuable guidance in improving the chance of success for cochlear gene therapy in human trials. A discussion on potential implications of translational knowledge gleaned from large numbers of advanced clinical trials of ocular gene therapy is therefore included.

Article

Increased irritability, anxiety, and immune reactivity in transgenic Huntington's disease monkeys

by Jessica Raper; Steven Bosinger; Zachary Johnson; Gregory Tharp; Sean Moran; Anthony Chan

2016

Subjects
  • Biology, Genetics
  • Health Sciences, Immunology
  • Biology, Neuroscience
  • File Download
  • View Abstract

Abstract:Close

Although the most notable clinical symptoms of Huntington's disease (HD) are motor disturbances and brain atrophy, other symptoms include cognitive dysfunction, emotional and hormonal dysregulation. Emotional dysregulation (irritability, anger/aggression, and anxiety) and increased inflammation are early emerging symptoms which can be detected decades before the onset of motor symptoms in HD patients. Despite the advances in understanding the genetic causes of HD there is still no cure or preventative treatment. Thus, to better understand the pathogenesis of HD and develop effective treatments, a holistic understanding of HD is needed, as well as animal models that replicate the full spectrum of HD symptoms. The current study examined the emotional, hormonal, and gene expression responses to an acute stressor of adult male transgenic HD rhesus monkeys (n = 2) as compared to wild-type controls (n = 2). Results revealed that HD monkeys expressed increased anxiety and irritability/aggression as compared to controls. Reactive cortisol response to the stressor was similar between groups. However, HD monkeys exhibited increased pro-inflammatory cytokines and higher induction of immune pathway genes as compared to controls. Overall, results reveal that HD monkeys exhibit these early emerging symptoms of HD and may be an effective animal model to facilitate the development of new therapeutics for HD patients.

Article

The Changing Face of Survival in Rett Syndrome and MECP2-Related Disorders

by Daniel Tarquinio; Wei Hou; Jeffrey L. Neul; Walter Kaufmann; Daniel G. Glaze; Kathleen J. Motil; Steven A. Skinner; Hye-Seung Lee; Alan K. Percy

2015

Subjects
  • Biology, Neuroscience
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

Purpose: Survival in Rett syndrome (RTT) remains unclear. Although early estimates were grim, more recent data suggest that survival into adulthood is typical. We aimed to define survival in RTT more clearly and identify risk factors for early death. Methods: Participants with clinical RTT or Methyl CpG Binding Protein 2 mutations without clinical RTT were recruited through the RTT Natural History study from 2006 to 2015. Clinical details were collected, and survival was determined using the Kaplan-Meier estimator. Risk factors were assessed using Cox proportional hazards models. Results: Among 1189 valid participants, 51 died (range 3.9–66.6 years) during the 9-year follow-up period. Those who died included 36 (3.9%) classic RTT females, 5 (5.9%) atypical severe RTT females, 1 (2.4%) non-RTT female, the single atypical severe male, 6 (30%) non-RTT males, and 2 (7.1%) DUP males. All atypical mild RTT females, DUP females and the single classic RTT male remain alive. Most deaths were due to cardiorespiratory issues. Only one died due to severe malnutrition, scoliosis, and extreme frailty. Survival for classic and atypical RTT was greater than 70% at 45 years. Overall severity and several modifiable risk factors, including ambulation, weight, and seizures, were associated with mortality in classic RTT. Conclusions: Survival in to the 5th decade is typical in RTT, and death due to extreme frailty has become rare. While the leading cause of death remains cardiorespiratory compromise, many risk factors for early death are modifiable. Intense therapeutic approaches could further improve the prognosis for patients with RTT.

Article

GPR37L1 modulates seizure susceptibility: Evidence from mouse studies and analyses of a human GPR37L1 variant

by Michelle M. Giddens; Jennifer Wong; Jason Schroeder; Emily G. Farrow; Brilee M. Smith; Sharon Owino; Sarah E. Soden; Rebecca C. Meyer; Carol Saunders; J.B. LePichon; David Weinshenker; Andrew Escayg; Randy Hall

2017

Subjects
  • Biology, Neuroscience
  • File Download
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Abstract:Close

Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G > T [Lys349Asn]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in Gpr37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy.

Article

Dysregulation of ErbB Receptor Trafficking and Signaling in Demyelinating Charcot-Marie-Tooth Disease

by Samuel M. Lee; Lih-Shen Chin; Lian Li

2017

Subjects
  • Health Sciences, Pharmacology
  • Biology, Neuroscience
  • File Download
  • View Abstract

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Charcot-Marie-Tooth (CMT) disease is the most common inherited peripheral neuropathy with the majority of cases involving demyelination of peripheral nerves. The pathogenic mechanisms of demyelinating CMT remain unclear, and no effective therapy currently exists for this disease. The discovery that mutations in different genes can cause a similar phenotype of demyelinating peripheral neuropathy raises the possibility that there may be convergent mechanisms leading to demyelinating CMT pathogenesis. Increasing evidence indicates that ErbB receptor-mediated signaling plays a major role in the control of Schwann cell-axon communication and myelination in the peripheral nervous system. Recent studies reveal that several demyelinating CMT-linked proteins are novel regulators of endocytic trafficking and/or phosphoinositide metabolism that may affect ErbB receptor signaling. Emerging data have begun to suggest that dysregulation of ErbB receptor trafficking and signaling in Schwann cells may represent a common pathogenic mechanism in multiple subtypes of demyelinating CMT. In this review, we focus on the roles of ErbB receptor trafficking and signaling in regulation of peripheral nerve myelination and discuss the emerging evidence supporting the potential involvement of altered ErbB receptor trafficking and signaling in demyelinating CMT pathogenesis and the possibility of modulating these trafficking and signaling processes for treating demyelinating peripheral neuropathy.

Article

Functional and Structural Impairments in the Perirhinal Cortex of a Mouse Model of CDKL5 Deficiency Disorder Are Rescued by a TrkB Agonist

by Elisa Ren; Vincenzo Roncace; Stefania Trazzi; Claudia Fuchs; Giorgio Medici; Laura Gennaccaro; Manuela Loi; Giuseppe Galvani; Keqiang Ye; Roberto Rimondini; Giorgio Aicardi; Elisabetta Ciani

2019

Subjects
  • Biology, Neuroscience
  • Engineering, Biomedical
  • Biophysics, Medical
  • File Download
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Abstract:Close

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a severe X-linked neurodevelopmental encephalopathy caused by mutations in the CDKL5 gene and characterized by early-onset epilepsy and intellectual and motor impairments. No cure is currently available for CDD patients, as limited knowledge of the pathology has hindered the development of therapeutics. Cdkl5 knockout (KO) mouse models, recently created to investigate the role of CDKL5 in the etiology of CDD, recapitulate various features of the disorder. Previous studies have shown alterations in synaptic plasticity and dendritic pattern in the cerebral cortex and in the hippocampus, but the knowledge of the molecular substrates underlying these alterations is still limited. Here, we have examined for the first time synaptic function and plasticity, dendritic morphology, and signal transduction pathways in the perirhinal cortex (PRC) of this mouse model. Being interconnected with a wide range of cortical and subcortical structures and involved in various cognitive processes, PRC provides a very interesting framework for examining how CDKL5 mutation leads to deficits at the synapse, circuit, and behavioral level. We found that long-term potentiation (LTP) was impaired, and that the TrkB/PLCγ 1 pathway could be mechanistically involved in this alteration. PRC neurons in mutant mice showed a reduction in dendritic length, dendritic branches, PSD-95-positive puncta, GluA2-AMPA receptor levels, and spine density and maturation. These functional and structural deficits were associated with impairment in visual recognition memory. Interestingly, an in vivo treatment with a TrkB agonist (the 7,8-DHF prodrug R13) to trigger the TrkB/PLCγ 1 pathway rescued defective LTP, dendritic pattern, PSD-95 and GluA2-AMPA receptor levels, and restored visual recognition memory in Cdkl5 KO mice. Present findings demonstrate a critical role of TrkB signaling in the synaptic development alterations due to CDKL5 mutation, and suggest the possibility of TrkB-targeted pharmacological interventions.

Article

Caspase-4 mediates cytoplasmic accumulation of TDP-43 in the primate brains

by Peng Yin; Xiangyu Guo; Weili Yang; Sen Yan; Su Yang; Ting Zhao; Qiang Sun; Yunbo Liu; Shihua Li; Xiao-Jiang Li

2019

Subjects
  • Biology, Neuroscience
  • Biology, Genetics
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Abstract:Close

The cytoplasmic accumulation of the nuclear TAR DNA-binding protein 43 (TDP-43) is a pathologic hallmark in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and other neurological disorders. However, most transgenic TDP-43 rodent models show predominant nuclear distribution of TDP-43 in the brain. By expressing mutant TDP-43 (M337V) in the brains of rhesus monkeys and mice, we verified that mutant TDP-43 is distributed in the cytoplasm of the monkey brain and that the majority of mutant TDP-43 remains in the nuclei of the mouse brain. The primate-specific caspase-4, but not mouse homologue caspase-11, could remove the NLS-containing N-terminal domain and generate fragmented TDP-43 that accumulates in the cytoplasm. Moreover, increased expression of caspase-4 in the monkey brain promotes the cytoplasmic accumulation of endogenous TDP-43, and suppressing caspase-4 reduces the cytoplasmic distribution of endogenous TDP-43 in cultured human neural cells. Our findings suggest that primate-specific caspase-4-mediated cleavage of TDP-43 accounts for its cytoplasmic mislocalization in the primate brains and may serve as a potential therapeutic target.
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