Royal Dutch Academy of Arts and science

Amsterdam, Netherlands

Royal Dutch Academy of Arts and science

Amsterdam, Netherlands

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Veloz M.F.V.,Erasmus University Rotterdam | Zhou K.,Erasmus University Rotterdam | Lin Z.,Erasmus University Rotterdam | De Zeeuw C.I.,Erasmus University Rotterdam | And 4 more authors.
PLoS ONE | Year: 2015

The enzyme glucocerebrosidase (GBA) hydrolyses glucosylceramide (GlcCer) in lysosomes. Markedly reduced GBA activity is associated with severe manifestations of Gaucher disease including neurological involvement. Mutations in the GBA gene have recently also been identified as major genetic risk factor for Parkinsonism. Disturbed metabolism of GlcCer may therefore play a role in neuropathology. Besides lysosomal GBA, cells also contain a non-lysosomal glucosylceramidase (GBA2). Given that the two β-glucosidases share substrates, we speculated that over-activity of GBA2 during severe GBA impairment might influence neuropathology. This hypothesis was studied in Niemann-Pick type C (Npc1-/-) mice showing secondary deficiency in GBA in various tissues. Here we report that GBA2 activity is indeed increased in the brain of Npc1-/- mice. We found that GBA2 is particularly abundant in Purkinje cells (PCs), one of the most affected neuronal populations in NPC disease. Inhibiting GBA2 in Npc1-/- mice with a brain-permeable low nanomolar inhibitor significantly improved motor coordination and extended lifespan in the absence of correction in cholesterol and ganglioside abnormalities. This trend was recapitulated, although not to full extent, by introducing a genetic loss of GBA2 in Npc1-/- mice. Our findings point to GBA2 activity as therapeutic target in NPC. © 2015 Marques et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Rahmati N.,Erasmus University Rotterdam | Kunzelmann K.,University of Regensburg | Xu J.,University of Cincinnati | Barone S.,University of Cincinnati | And 6 more authors.
Pflugers Archiv European Journal of Physiology | Year: 2013

SLC26A11 (human)/Slc26a11 (mouse), also known as kidney brain anion transporter (KBAT), is a member of the SLC26 anion transporter family and shows abundant mRNA expression in the brain. However, its exact cellular distribution and subcellular localization in the brain and its functional identity and possible physiological roles remain unknown. Expression and immunostaining studies demonstrated that Slc26a11 is abundantly expressed in the cerebellum, with a predominant expression in Purkinje cells. Lower expression levels were detected in hippocampus, olfactory bulb, cerebral cortex, and subcortical structures. Patch clamp studies in HEK293 cells transfected with mouse cDNA demonstrated that Slc26a11 can function as a chloride channel that is active under basal conditions and is not regulated by calcium, forskolin, or co-expression with cystic fibrosis transmembrane regulator. Single and double immunofluorescent labeling studies demonstrated the localization of vacuolar (V) H+-ATPase and Slc26a11 (KBAT) in the plasma membrane in Purkinje cells. Functional studies in HEK293 cells indicated that transfection with Slc26a11 stimulated acid transport via endogenous V H+-ATPase. We conclude that Slc26a11 (KBAT) is prominently distributed in output neurons of various subcortical and cortical structures in the central nervous system, with specific expression in Purkinje cells and that it may operate as a chloride channel regulating acid translocation by H+-ATPase across the plasma membrane and in intracellular compartments. © 2013 Springer-Verlag Berlin Heidelberg.


Sepulveda-Falla D.,University of Hamburg | Barrera-Ocampo A.,University of Hamburg | Hagel C.,University of Hamburg | Korwitz A.,University of Cologne | And 13 more authors.
Journal of Clinical Investigation | Year: 2014

Familial Alzheimer's disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca 2+ channels IP3Rs and CACNA1A were downregulated, and Ca 2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.


Lapid-Gortzak R.,University of Amsterdam | Labuz G.,Rotterdam Ophthalmic Institute | Van Der Meulen I.J.,University of Amsterdam | Van Der Linden J.W.,Retina Total Eye Care | And 2 more authors.
Journal of Refractive Surgery | Year: 2015

PURPOSE: To evaluate differences in straylight between eyes implanted with a hydrophilic multifocal IOL (Seelens MF; Hanita Lenses, Hanita, Israel) and a hydrophobic multifocal IOL (SN6AD1; Alcon Laboratories, Inc., Fort Worth, TX). METHODS: In a prospective cohort study, routinely obtained straylight measurements (C-Quant; Oculus Optikgeräte, Wetzlar, Germany) 3 months after standard phacoemulsification for either cataract or refractive lens procedures were compared. Patients were implanted with either the SeeLens MF IOL or the SN6AD1 IOL. Postoperative straylight values, visual acuity, and refractive outcomes were compared. RESULTS: The SeeLens MF IOL was implanted in 84 eyes and the SN6AD1 IOL in 79 eyes. The difference in straylight was 0.08 (P = .01), with the SeeLens MF IOL having less straylight. Postoperative CDVA was logMAR -0.03 ± 0.06 in the SeeLens MF group, and logMAR -0.02 ± 0.08 in the SN6AD1 group. Mean postoperative refraction was +0.01 ± 0.43 and +0.06 ± 0.35 D, respectively. CONCLUSIONS: The Seelens MF IOL showed a straylight of log(s) 0.08 lower than the SN6AD1 IOL. In terms of spherical equivalent and visual acuity the lenses performed equally. More study will aid in understanding the causes and clinical impact of this difference. © SLACK Incorporated.


Lapid-Gortzak R.,University of Amsterdam | Van Der Meulen I.J.E.,University of Amsterdam | Van Der Linden J.W.,Retina Total Eye Care | Mourits M.P.,University of Amsterdam | Van Den Berg T.J.T.P.,Royal Dutch Academy of Arts and science
Journal of Cataract and Refractive Surgery | Year: 2014

Purpose To report the outcomes of changes in straylight before and after phacoemulsification in eyes with preoperative corrected distance visual acuity (CDVA) better than 0.1 logMAR. Setting Private refractive surgery clinic, Driebergen, the Netherlands. Design Cohort study. Methods Standard phacoemulsification with implantation of a monofocal or multifocal intraocular lens (IOL) was performed. Preoperative and 3-month postoperative straylight values, CDVA, and refractive error were compared. Results The study enrolled 160 eyes (89 patients). The mean CDVA was 0.02 ± 0.05 logMAR (range -0.1 to 0.1 logMAR) preoperatively and 0.00 ± 0.04 logMAR (range -0.1 to 0.2 logMAR) postoperatively. The mean preoperative straylight was 1.21 ± 0.20 log(s) (range 0.80 to 1.74 log[s]) and 1.11 ± 1.16 log(s) (range 0.76 to 1.63 log[s]), respectively; the improvement was statistically significant. There was a correlation between high preoperative straylight values and postoperative improvement in straylight values. Conclusions In eyes with relatively good CDVA of 0.1 logMAR or better (decimal 0.8 or better; Snellen 20/25 or better), straylight improved by 0.10 log(s) after cataract surgery. A subgroup of 44 eyes had an improvement of more than 0.20 log(s), which is comparable to a 2-line improvement on the vision chart. Financial Disclosure(s) Proprietary or commercial disclosures are listed after the references. © 2014 ASCRS and ESCRS.


Broersen R.,Royal Dutch Academy of Arts and science | Broersen R.,Erasmus Medical Center | Onuki Y.,Royal Dutch Academy of Arts and science | Abdelgabar A.R.,Royal Dutch Academy of Arts and science | And 11 more authors.
PLoS ONE | Year: 2016

Many daily life activities demand precise integration of spatial and temporal information of sensory inputs followed by appropriate motor actions. This type of integration is carried out in part by the cerebellum, which has been postulated to play a central role in learning and timing of movements. Cerebellar damage due to atrophy or lesions may compromise forward- model processing, in which both spatial and temporal cues are used to achieve prediction for future motor states. In the present study we sought to further investigate the cerebellar contribution to predictive and reactive motor timing, as well as to learning of sequential order and temporal intervals in these tasks. We tested patients with spinocerebellar ataxia type 6 (SCA6) and healthy controls for two related motor tasks; one requiring spatio-temporal prediction of dynamic visual stimuli and another one requiring reactive timing only. We found that healthy controls established spatio-temporal prediction in their responses with high temporal precision, which was absent in the cerebellar patients. SCA6 patients showed lower predictive motor timing, coinciding with a reduced number of correct responses during the 'anticipatory' period on the task. Moreover, on the task utilizing reactive motor timing functions, control participants showed both sequence order and temporal interval learning, whereas patients only showed sequence order learning. These results suggest that SCA6 affects predictive motor timing and temporal interval learning. Our results support and highlight cerebellar contribution to timing and argue for cerebellar engagement during spatio-temporal prediction of upcoming events. © 2016 Broersen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Voogd J.,Erasmus University Rotterdam | Schraa-Tam C.K.L.,Erasmus University Rotterdam | Van Der Geest J.N.,Erasmus University Rotterdam | De Zeeuw C.I.,Erasmus University Rotterdam | De Zeeuw C.I.,Royal Dutch Academy of Arts and science
Cerebellum | Year: 2012

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula- nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed. ©Springer Science+Business Media, LLC 2011.


Jaarsma D.,Erasmus Medical Center | Van Den Berg R.,Erasmus Medical Center | Van Den Berg R.,University Utrecht | Wulf P.S.,Erasmus Medical Center | And 13 more authors.
Nature Communications | Year: 2014

Bicaudal-D (BICD) belongs to an evolutionary conserved family of dynein adaptor proteins. It was first described in Drosophila as an essential factor in fly oogenesis and embryogenesis. Missense mutations in a human BICD homologue, BICD2, have been linked to a dominant mild early onset form of spinal muscular atrophy. Here we further examine the in vivo function of BICD2 in Bicd2 knockout mice. BICD2-deficient mice develop disrupted laminar organization of cerebral cortex and the cerebellum, pointing to impaired radial neuronal migration. Using astrocyte and granule cell specific inactivation of BICD2, we show that the cerebellar migration defect is entirely dependent upon BICD2 expression in Bergmann glia cells. Proteomics analysis reveals that Bicd2 mutant mice have an altered composition of extracellular matrix proteins produced by glia cells. These findings demonstrate an essential non-cell-autonomous role of BICD2 in neuronal cell migration, which might be connected to cargo trafficking pathways in glia cells. © 2014 Macmillan Publishers Limited. All rights reserved.


Lapid-Gortzak R.,Retina Total Eye Care | Lapid-Gortzak R.,University of Amsterdam | Van Der Meulen I.J.E.,Retina Total Eye Care | Van Der Meulen I.J.E.,University of Amsterdam | And 2 more authors.
Journal of Cataract and Refractive Surgery | Year: 2011

In a patient with complaints of photophobia and an ocular deviation, straylight was found to be increased to 1.61 (log[s]), which is 5 times the normal value. The only relative clinical finding was the edge of a too small posterior capsulotomy. Visual acuity was normal. Six weeks after the posterior capsulotomy was widened to a diameter of 6.0 mm with a neodymium:YAG laser, the symptoms were resolved and the patient was satisfied. Straylight may manifest clinically as complaints of photophobia. Straylight increase, which can be related to slitlamp findings, may lead to an interventional decision. Our clinical decision-making was also guided by straylight measurements and proved to be crucial in resolving the patient's complaints. More study of clinical situations in which straylight measurement can be used is needed. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. Additional disclosures are in the footnotes. © 2011 ASCRS and ESCRS.


Coesmans M.,Erasmus University Rotterdam | Coesmans M.,Delta Psychiatric Center | Roder C.H.,Erasmus University Rotterdam | Smit A.E.,Erasmus University Rotterdam | And 5 more authors.
Journal of Psychiatry and Neuroscience | Year: 2014

Background: The notion that cerebellar deficits may underlie clinical symptoms in people with schizophrenia is tested by evaluating 2 forms of cerebellar learning in patients with recent-onset schizophrenia. A potential medication effect is evaluated by including patients with or without antipsychotics. Methods: We assessed saccadic eye movement adaptation and eyeblink conditioning in men with recentonset schizophrenia who were taking antipsychotic medication or who were antipsychotic-free and in age-matched controls. Results: We included 39 men with schizophrenia (10 who were taking clozapine, 16 who were taking haloperidol and 13 who were antipsychoticfree) and 29 controls in our study. All participants showed significant saccadic adaptation. Adaptation strength did not differ between healthy controls and men with schizophrenia. The speed of saccade adaptation, however, was significantly lower in men with schizophrenia. They showed a significantly lower increase in the number of conditioned eyeblink responses. Over all experiments, no consist - ent effects of medication were observed. These outcomes did not correlate with age, years of education, psychopathology or dose of anti psychotics. Limitations: As patients were not randomized for treatment, an influence of confounding variables associated with medi - cation status cannot be excluded. Individual patients also varied along the schizophrenia spectrum despite the relative homogeneity with respect to onset of illness and short usage of medication. Finally, the relatively small number of participants may have concealed effects as a result of insufficient statistical power. Conclusion: We found several cerebellar learning deficits in men with schizophrenia that we cannot attribute to the use of antipsychotics. Although this finding, combined with the fact that deficits are already present in patients with recent-onset schizophrenia, could suggest that cerebellar impairments are a trait deficit in people with schizophrenia. This should be confirmed in longitudinal studies. © 2014 Canadian Medical Association.

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