Publications by authors named "Benedikt Bader"

35 Publications

Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis.

Mol Genet Genomic Med 2020 09 14;8(9):e1179. Epub 2020 Feb 14.

Neurologische Klinik und Poliklinik, Ludwigs-Maximilians Universität München, Munich, Germany.

Background: Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough.

Methods: Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot.

Results: We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings.

Conclusion: Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507471PMC
September 2020

Subcortical neurodegeneration in chorea: Similarities and differences between chorea-acanthocytosis and Huntington's disease.

Parkinsonism Relat Disord 2018 04 10;49:54-59. Epub 2018 Jan 10.

Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität München, Germany.

Introduction: Chorea-acanthocytosis (ChAc) and Huntington's disease (HD) are neurodegenerative conditions that share clinical and neuropathological features, despite their distinct genetic etiologies.

Methods: In order to compare these neuropathologies, serial gallocyanin-stained brain sections from three subjects with ChAc were analyzed and compared with our previous studies of eight HD cases, in addition to three hemispheres from two male controls.

Results: Astrogliosis was much greater in the ChAc striatum, as compared to that found in HD, with dramatic increase in total striatal glia numbers and the number of glia per striatal neuron. Striatal astrocytes are most likely derived from the striatal subependymal layer in ChAc, which showed massive proliferation. The thalamic centromedian-parafascicular complex is reciprocally connected to the striatum and is more heavily affected in HD than in ChAc.

Conclusion: The distinct patterns of selective vulnerability and gliosis observed in HD and ChAc challenge simplistic views on the pathogenesis of these two diseases with rather similar clinical signs. The particular roles played by astroglia in ChAc and in HD clearly need to be elucidated in more detail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2018.01.009DOI Listing
April 2018

A new molecular link between defective autophagy and erythroid abnormalities in chorea-acanthocytosis.

Blood 2016 12 14;128(25):2976-2987. Epub 2016 Oct 14.

Department of Medicine, University of Verona and Azienda ospedaliera Universitaria Integrata di Verona, Verona, Italy.

Chorea-acanthocytosis is one of the hereditary neurodegenerative disorders known as the neuroacanthocytoses. Chorea-acanthocytosis is characterized by circulating acanthocytes deficient in chorein, a protein of unknown function. We report here for the first time that chorea-acanthocytosis red cells are characterized by impaired autophagy, with cytoplasmic accumulation of active Lyn and of autophagy-related proteins Ulk1 and Atg7. In chorea-acanthocytosis erythrocytes, active Lyn is sequestered by HSP90-70 to form high-molecular-weight complexes that stabilize and protect Lyn from its proteasomal degradation, contributing to toxic Lyn accumulation. An interplay between accumulation of active Lyn and autophagy was found in chorea-acanthocytosis based on Lyn coimmunoprecipitation with Ulk1 and Atg7 and on the presence of Ulk1 in Lyn-containing high-molecular-weight complexes. In addition, chorein associated with Atg7 in healthy but not in chorea-acanthocytosis erythrocytes. Electron microscopy detected multivesicular bodies and membrane remnants only in circulating chorea-acanthocytosis red cells. In addition, reticulocyte-enriched chorea-acanthocytosis red cell fractions exhibited delayed clearance of mitochondria and lysosomes, further supporting the impairment of authophagic flux. Because autophagy is also important in erythropoiesis, we studied in vitro CD34-derived erythroid precursors. In chorea-acanthocytosis, we found (1) dyserythropoiesis; (2) increased active Lyn; (3) accumulation of a marker of autophagic flux and autolysososme degradation; (4) accumlation of Lamp1, a lysosmal membrane protein, and LAMP1-positive aggregates; and (5) reduced clearance of lysosomes and mitochondria. Our results uncover in chorea-acanthocytosis erythroid cells an association between accumulation of active Lyn and impaired autophagy, suggesting a link between chorein and autophagic vesicle trafficking in erythroid maturation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-07-727321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5179337PMC
December 2016

The association of aphasia and right-sided motor impairment in corticobasal syndrome.

J Neurol 2015 Oct 5;262(10):2241-6. Epub 2015 Jul 5.

Neurology Department, Ludwig-Maximilians-Universität München, Marchioninistr. 15, 81377, Munich, Germany.

Corticobasal syndrome is defined clinically on the basis of symptoms and findings related to dysfunction of the cerebral cortex and the basal ganglia. Usually, marked asymmetry of motor findings is observed. Although aphasia has now been recognized as a frequent feature of corticobasal syndrome, it remains unclear whether it is usually associated with right-sided motor symptoms, pointing to the involvement of the left hemisphere. Hence, we set out to examine the relationship between the presence of language symptoms and the side affected by extrapyramidal symptoms. We analyzed the electronic care records of patients seen in the years 2003-2013 in the Neurology Department of the University Hospital of Munich. The diagnosis of corticobasal syndrome was discussed in ninety-two individuals. Of those, 38 cases fulfilled diagnostic criteria for corticobasal syndrome. Aphasia correlated highly with a predominant right-sided movement disorder (p = 0.002). In contrast, it was less common in patients with left-sided motor presentation. Dysarthria did not show a preferential correlation (p = 0.25). Our analysis suggests a characteristic presentation of corticobasal syndrome in which motor dysfunction of the right side of the body is associated with aphasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-015-7833-1DOI Listing
October 2015

Neuroacanthocytosis in china: a review of published reports.

Tremor Other Hyperkinet Mov (N Y) 2014 31;4:248. Epub 2014 Oct 31.

Neurologische Klinik, Klinikum der Universität München, 81377 München, Germany.

Background: Neuroacanthocytosis (NA) syndromes are a group of rare diseases characterized by the presence of acanthocytes and neuronal multisystem pathology, including chorea-acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington's disease-like 2 (HDL-2), and pantothenate kinase-associated neurodegeneration (PKAN). China has the largest population in the world, which makes it a good location for investigating rare diseases like NA.

Methods: We searched Medline, ISI Proceedings, China National Knowledge Infrastructure, and Wanfang Data for literature published through December 31, 2013 for all the published Chinese NA case reports and extracted the clinical and laboratory findings.

Results: A total of 42 studies describing 66 cases were found to be eligible for inclusion. Age of symptom onset ranged from 5 to 74 years. The most common findings included hyperkinetic movements (88%), orofacial dyskinesia (80%), dystonia (67%), and dysarthria (68%), as well as caudate atrophy or enlarged lateral ventricles on neuroimaging (64%), and elevated creatine kinase (52%). Most cases were not confirmed by any specific molecular tests. Only two cases were genetically studied and diagnosed as ChAc or MLS.

Discussion: In view of the prevalence of NA syndromes in other countries, the number of patients in China appears to be underestimated. Chinese NA patients may benefit from the establishment of networks that offer specific diagnoses and care for rare diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7916/D8Q23XDXDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219110PMC
November 2014

Modelling Ser129 phosphorylation inhibits membrane binding of pore-forming alpha-synuclein oligomers.

PLoS One 2014 9;9(6):e98906. Epub 2014 Jun 9.

Center for Neuropathology and Prion Research, Ludwig-Maximilians-University, Munich, Germany.

Background: In several neurodegenerative diseases, hyperphosphorylation at position Ser129 is found in fibrillar deposits of alpha-synuclein (asyn), implying a pathophysiological role of asyn phosphorylation in neurodegeneration. However, recent animal models applying asyn phosphorylation mimics demonstrated a protective effect of phosphorylation. Since metal-ion induced asyn oligomers were identified as a potential neurotoxic aggregate species with membrane pore-forming abilities, the current study was undertaken to determine effects of asyn phosphorylation on oligomer membrane binding.

Methods: We investigated the influence of S129 phosphorylation on interactions of metal-ion induced asyn oligomers with small unilamellar lipid vesicles (SUV) composed of POPC and DPPC applying the phosphorylation mimic asyn129E. Confocal single-particle fluorescence techniques were used to monitor membrane binding at the single-particle level.

Results: Binding of asyn129E monomers to gel-state membranes (DPPC-SUV) is slightly reduced compared to wild-type asyn, while no interactions with membranes in the liquid-crystalline state (POPC-SUV) are seen for both asyn and asyn129E. Conversely, metal-ion induced oligomer formation is markedly increased in asyn129E. Surprisingly, membrane binding to POPC-SUV is nearly absent in Fe(3+) induced asyn129E oligomers and markedly reduced in Al(3+) induced oligomers.

Conclusion: The protective effect of pseudophosphorylation seen in animal models may be due to impeded oligomer membrane binding. Phosphorylation at Ser129 may thus have a protective effect against neurotoxic asyn oligomers by preventing oligomer membrane binding and disruption of the cellular electrophysiological equilibrium. Importantly, these findings put a new complexion on experimental pharmaceutical interventions against POLO-2 kinase.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0098906PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049638PMC
June 2015

Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis.

PLoS One 2013 5;8(11):e79241. Epub 2013 Nov 5.

Service de Neurologie, CHU Bordeaux, Bordeaux, France ; Service de Neurologie, CH François Mitterrand, Pau, France.

Background: Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS.

Methods: Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months).

Results: Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery.

Conclusion: This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079241PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3818425PMC
August 2014

Alterations of red cell membrane properties in neuroacanthocytosis.

PLoS One 2013 3;8(10):e76715. Epub 2013 Oct 3.

Max F. Perutz Laboratories, Medical University of Vienna, Vienna, Austria.

Neuroacanthocytosis (NA) refers to a group of heterogenous, rare genetic disorders, namely chorea acanthocytosis (ChAc), McLeod syndrome (MLS), Huntington's disease-like 2 (HDL2) and pantothenate kinase associated neurodegeneration (PKAN), that mainly affect the basal ganglia and are associated with similar neurological symptoms. PKAN is also assigned to a group of rare neurodegenerative diseases, known as NBIA (neurodegeneration with brain iron accumulation), associated with iron accumulation in the basal ganglia and progressive movement disorder. Acanthocytosis, the occurrence of misshaped erythrocytes with thorny protrusions, is frequently observed in ChAc and MLS patients but less prevalent in PKAN (about 10%) and HDL2 patients. The pathological factors that lead to the formation of the acanthocytic red blood cell shape are currently unknown. The aim of this study was to determine whether NA/NBIA acanthocytes differ in their functionality from normal erythrocytes. Several flow-cytometry-based assays were applied to test the physiological responses of the plasma membrane, namely drug-induced endocytosis, phosphatidylserine exposure and calcium uptake upon treatment with lysophosphatidic acid. ChAc red cell samples clearly showed a reduced response in drug-induced endovesiculation, lysophosphatidic acid-induced phosphatidylserine exposure, and calcium uptake. Impaired responses were also observed in acanthocyte-positive NBIA (PKAN) red cells but not in patient cells without shape abnormalities. These data suggest an "acanthocytic state" of the red cell where alterations in functional and interdependent membrane properties arise together with an acanthocytic cell shape. Further elucidation of the aberrant molecular mechanisms that cause this acanthocytic state may possibly help to evaluate the pathological pathways leading to neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0076715PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789665PMC
April 2014

Chorea-acanthocytosis: report of three cases from Iran.

Arch Iran Med 2012 Dec;15(12):780-2

Movement Disorders Clinic, Rasool Akram Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Chorea-acanthocythosis (ChAc) is an inherited neurodegenerative disorder characterized by movement disorders, neuropsychiatric disturbances, neuropathy, myopathy, seizures and acanthocytosis accompanied by an elevated serum creatine kinase (CK) level. Its causative gene (VPS13A) produces chorein which is absent in ChAc patients as evaluated by Western blot assay. We report the first three Iranian patients whose disease has been confirmed by chorein Western blot. Our cases presented with heterogeneous courses of ChAc. A high sense of clinical awareness in approaching patients with deteriorating and/or multiple abnormal movements that are accompanied by other neurological signs such as neuropathy, myopathy, seizures and high serum CK level will support an early diagnosis of this disease. We also emphasize on the presence of axial flexion/extension spasms as a good clinical sign for narrowing differential diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/0121512/AIM.0013DOI Listing
December 2012

Synergistic influence of phosphorylation and metal ions on tau oligomer formation and coaggregation with α-synuclein at the single molecule level.

Mol Neurodegener 2012 Jul 23;7:35. Epub 2012 Jul 23.

Center for Neuropathology and Prion Research, Ludwig-Maximilians-Universität, Feodor-Lynen-Str, 23, 81377, Munich, Germany.

Background: Fibrillar amyloid-like deposits and co-deposits of tau and α-synuclein are found in several common neurodegenerative diseases. Recent evidence indicates that small oligomers are the most relevant toxic aggregate species. While tau fibril formation is well-characterized, factors influencing tau oligomerization and molecular interactions of tau and α-synuclein are not well understood.

Results: We used a novel approach applying confocal single-particle fluorescence to investigate the influence of tau phosphorylation and metal ions on tau oligomer formation and its coaggregation with α-synuclein at the level of individual oligomers. We show that Al3+ at physiologically relevant concentrations and tau phosphorylation by GSK-3β exert synergistic effects on the formation of a distinct SDS-resistant tau oligomer species even at nanomolar protein concentration. Moreover, tau phosphorylation and Al3+ as well as Fe3+ enhanced both formation of mixed oligomers and recruitment of α-synuclein in pre-formed tau oligomers.

Conclusions: Our findings provide a new perspective on interactions of tau phosphorylation, metal ions, and the formation of potentially toxic oligomer species, and elucidate molecular crosstalks between different aggregation pathways involved in neurodegeneration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/1750-1326-7-35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472288PMC
July 2012

Autosomal recessive transmission of chorea-acanthocytosis confirmed.

Acta Neuropathol 2012 Jun 3;123(6):905-6. Epub 2012 Apr 3.

Neurologische Klinik und Poliklinik, Klinikum der Universität München, Munich, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-012-0971-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629413PMC
June 2012

Computational identification of phospho-tyrosine sub-networks related to acanthocyte generation in neuroacanthocytosis.

PLoS One 2012 15;7(2):e31015. Epub 2012 Feb 15.

Department of Medicine, University of Verona, Verona, Italy.

Acanthocytes, abnormal thorny red blood cells (RBC), are one of the biological hallmarks of neuroacanthocytosis syndromes (NA), a group of rare hereditary neurodegenerative disorders. Since RBCs are easily accessible, the study of acanthocytes in NA may provide insights into potential mechanisms of neurodegeneration. Previous studies have shown that changes in RBC membrane protein phosphorylation state affect RBC membrane mechanical stability and morphology. Here, we coupled tyrosine-phosphoproteomic analysis to topological network analysis. We aimed to predict signaling sub-networks possibly involved in the generation of acanthocytes in patients affected by the two core NA disorders, namely McLeod syndrome (MLS, XK-related, Xk protein) and chorea-acanthocytosis (ChAc, VPS13A-related, chorein protein). The experimentally determined phosphoproteomic data-sets allowed us to relate the subsequent network analysis to the pathogenetic background. To reduce the network complexity, we combined several algorithms of topological network analysis including cluster determination by shortest path analysis, protein categorization based on centrality indexes, along with annotation-based node filtering. We first identified XK- and VPS13A-related protein-protein interaction networks by identifying all the interactomic shortest paths linking Xk and chorein to the corresponding set of proteins whose tyrosine phosphorylation was altered in patients. These networks include the most likely paths of functional influence of Xk and chorein on phosphorylated proteins. We further refined the analysis by extracting restricted sets of highly interacting signaling proteins representing a common molecular background bridging the generation of acanthocytes in MLS and ChAc. The final analysis pointed to a novel, very restricted, signaling module of 14 highly interconnected kinases, whose alteration is possibly involved in generation of acanthocytes in MLS and ChAc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031015PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280254PMC
June 2012

Chorea-acanthocytosis genotype in the original critchley kentucky neuroacanthocytosis kindred.

Arch Neurol 2011 Oct;68(10):1330-3

The Wellcome Trust Centre for Human Genetics, Oxford, England.

Objective: To determine the molecular nature of the neurological disease in the seminal family reported by Critchley et al in the 1960s, characterized by a hyperkinetic movement disorder and the appearance of acanthocytosis on peripheral blood smear. The eponym Levine-Critchley syndrome, subsequently termed neuroacanthocytosis, has been applied to symptomatically similar, but genetically distinct, disorders, resulting in clinical and diagnostic confusion.

Design: DNA analysis.

Setting: Molecular biology research laboratories.

Participants: First- and second-degree relatives of the original Critchley et al proband from Kentucky.

Main Outcome Measures: Mutations in the VPS13A gene.

Results: A mutation was identified in the VPS13A gene, responsible for autosomal recessive chorea-acanthocytosis. Haplotype reconstruction suggested that this mutation was homozygous in the proband.

Conclusion: These findings strongly support the diagnosis of chorea-acanthocytosis as the disorder described in the original report.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archneurol.2011.239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615612PMC
October 2011

Erythrocyte membrane changes of chorea-acanthocytosis are the result of altered Lyn kinase activity.

Blood 2011 Nov 27;118(20):5652-63. Epub 2011 Sep 27.

Department of Medicine, University of Verona, Piazzale Lo Scuro 10, Verona, Italy.

Acanthocytic RBCs are a peculiar diagnostic feature of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder. Although recent years have witnessed some progress in the molecular characterization of ChAc, the mechanism(s) responsible for generation of acanthocytes in ChAc is largely unknown. As the membrane protein composition of ChAc RBCs is similar to that of normal RBCs, we evaluated the tyrosine (Tyr)-phosphorylation profile of RBCs using comparative proteomics. Increased Tyr phosphorylation state of several membrane proteins, including band 3, β-spectrin, and adducin, was noted in ChAc RBCs. In particular, band 3 was highly phosphorylated on the Tyr-904 residue, a functional target of Lyn, but not on Tyr-8, a functional target of Syk. In ChAc RBCs, band 3 Tyr phosphorylation by Lyn was independent of the canonical Syk-mediated pathway. The ChAc-associated alterations in RBC membrane protein organization appear to be the result of increased Tyr phosphorylation leading to altered linkage of band 3 to the junctional complexes involved in anchoring the membrane to the cytoskeleton as supported by coimmunoprecipitation of β-adducin with band 3 only in ChAc RBC-membrane treated with the Lyn-inhibitor PP2. We propose this altered association between membrane skeleton and membrane proteins as novel mechanism in the generation of acanthocytes in ChAc.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2011-05-355339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217364PMC
November 2011

Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype.

Arq Neuropsiquiatr 2011 06;69(3):419-23

Department of Neuroscience and Behaviour Sciences, Ribeirão Preto School of Medicine, University of São Paulo, Brazil.

Huntington's disease (HD) is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntington's disease-like 2 (HDL2), spinocerebellar ataxia (SCA) 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and chorea-acanthocytosis (ChAc) among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3% of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1590/s0004-282x2011000400002DOI Listing
June 2011

Single particle analysis of tau oligomer formation induced by metal ions and organic solvents.

Biochem Biophys Res Commun 2011 Jul 24;411(1):190-6. Epub 2011 Jun 24.

Zentrum für Neuropathologie und Prionforschung, Ludwig-Maximilians-Universität, München, Germany.

Pathological aggregates of tau protein are found in several neurodegenerative diseases termed 'tauopathies'. Increasing evidence indicates that tau oligomer species rather than the large amyloid cytoplasmic inclusions relevant for histopathological diagnosis might be crucial for cellular damage and neurodegeneration. Trivalent metal ions and polyanionic structures like heparin or arachidonic acid have been shown to induce tau aggregation. However, little is known about early processes of tau aggregation. In this study, we applied fluorescence correlation spectroscopy (FCS) and scanning for intensely fluorescent targets (SIFT) to investigate oligomer formation of tau protein at nanomolar protein concentrations at the single-particle level. Our results indicate that the formation of distinct tau oligomers is induced by the trivalent metal ions Fe(3+) and Al(3+) and by organic solvents like DMSO, respectively. In contrast, bivalent metal ions (Cu(2+), Zn(2+), Mn(2+), Ca(2+), Mg(2+)) had no effect. While DMSO-induced small tau oligomers are relatively stable in solution, dynamic remodeling can be initiated by non-ionic detergents. Moreover Al(3+) induces rapid formation of a different oligomer species of larger size. Our results provide further insights into early tau oligomerization and aggregation dynamics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2011.06.135DOI Listing
July 2011

Bilateral temporal lobe epilepsy confirmed with intracranial EEG in chorea-acanthocytosis.

Seizure 2011 May 19;20(4):340-2. Epub 2011 Jan 19.

Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität, Marchioninistr. 15, 81377 München, Germany.

Chorea-acanthocytosis (ChAc) is an uncommon basal ganglia disorder, in which the movement disorder element may be obscured by the predominance of seizures. We report a pertinent case of a patient who had undergone extensive evaluation for epilepsy, including intracranial EEG before finally the diagnosis of ChAc was made and confirmed by Western blot. We suggest that in patients with epilepsy, particularly of temporal lobe origin and with onset in the third decade with inconclusive findings on clinical examination and neuroimaging such as dyskinesias, dystonia and basal ganglia involvement, ChAc should be considered.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2010.12.007DOI Listing
May 2011

Generation of ferric iron links oxidative stress to α-synuclein oligomer formation.

J Parkinsons Dis 2011 ;1(2):205-16

Neurology Department, Ludwig-Maximilians-University Munich, Munich, Germany.

Background: Synucleinopathies such as Parkinson's disease are characterized by the deposition of aggregated α-synuclein in affected brain areas. As genes involved in mitochondrial function, mitochondrial toxins, and age-related mitochondrial impairment have been implicated in Parkinson's disease pathogenesis, an increase in reactive oxygen species resulting from mitochondrial dysfunction has been speculated to induce α-synuclein aggregation. In vitro, pore-forming, SDS-resistant α-synuclein oligomers are formed in presence of ferric iron and may represent an important toxic particle species.

Methodology/principal Findings: We investigated the interplay of reactive oxygen species, antioxidants and iron oxidation state in regard to α-synuclein aggregation using confocal single particle fluorescence spectroscopy, Phenanthroline spectrometry and thiobarbituric acid reactive substances assay. We found that the formation of α-synuclein oligomers in presence of Fe³⁺ is due to a direct interaction. In contrast, oxidizing agents and hydroxyl radicals generated in the Fenton reaction did not directly affect α-synuclein oligomerization. However, reactive oxygen species could enhance aggregation via oxidation of ferrous to ferric iron when iron ions were present.

Conclusions/significance: Our data thus indicate that oxidative stress affects α-synuclein aggregation via oxidation of iron to the ferric state. This provides a new perspective on the role of mitochondrial toxins and mitochondrial dysfunction in the pathogenesis of Parkinson's disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/JPD-2011-11040DOI Listing
June 2014

Characteristic head drops and axial extension in advanced chorea-acanthocytosis.

Mov Disord 2010 Jul;25(10):1487-91

Sobell Department of Motor Neuroscience and Movement Disorders, UCL, Institute of Neurology, Queen Square, London, United Kingdom.

Chorea-acanthocytosis is a rare autosomal recessive neurodegenerative disorder with a complex clinical presentation comprising of a mixed movement disorder (mostly chorea and dystonia), seizures, neuropathy and myopathy, autonomic features as well as dementia and psychiatric features. Because the differential diagnosis is wide, clinical clues and red flags are important. We report here our observation of characteristic neck and trunk flexion and extension spasms in four cases with advanced chorea-acanthocytosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.23052DOI Listing
July 2010

CADASIL mutations enhance spontaneous multimerization of NOTCH3.

Hum Mol Genet 2009 Aug 5;18(15):2761-7. Epub 2009 May 5.

Department of Neurology, Ludwig-Maximilians-University, Munich, Germany.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of stroke and vascular dementia. Disease-causing mutations invariably affect cysteine residues within epidermal growth factor-like repeat domains in the extracellular domain of the NOTCH3 receptor (N3(ECD)). The biochemical and histopathological hallmark of CADASIL is the accumulation of N3(ECD) at the cell surface of vascular smooth muscle cells which degenerate over the course of the disease. The molecular mechanisms leading to N3(ECD) accumulation remain unknown. Here we show that both wild-type and CADASIL-mutated N3(ECD) spontaneously form oligomers and higher order multimers in vitro and that multimerization is mediated by disulfide bonds. Using single-molecule analysis techniques ('scanning for intensely fluorescent targets'), we demonstrate that CADASIL-associated mutations significantly enhance multimerization compared with wild-type. Taken together, our results for the first time provide experimental evidence for N3 self-association and strongly argue for a neomorphic effect of CADASIL mutations in disease pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddp211DOI Listing
August 2009

Chorea-acanthocytosis: report of two Brazilian cases.

Mov Disord 2008 Oct;23(14):2090-3

Department of Neurology, Ribeirao Preto School of Medicine, Ribeirao Preto, Brazil.

Chorea-acanthocytosis (ChAc) is a neurodegenerative disorder characterized by chorea, neuropsychiatric disturbances and acanthocytosis, caused by mutations of VPS13A. This gene produces the protein chorein which is absent in patients with ChAc on Western blot assay. We report the first two Brazilian patients with ChAc confirmed by chorein detection. Patient 1 is a 36-year-old man with chorea, epilepsy, myopathy, and suicidal ideation. Patient 2 is a 60-year-old woman with a 30 year history of psychiatric disturbances, epilepsy, choreic movements, and myopathy. Both patients had acanthocytosis, elevated creatine kinase (CK), and absence of chorein on Western blot analysis. The presence of chorea and neuropsychiatric disturbances associated with elevated CK levels, epilepsy, hyporeflexia, and acanthocytosis suggests the diagnosis of ChAc. Chorein assay of peripheral blood confirms the diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mds.22305DOI Listing
October 2008

Dominant transmission of chorea-acanthocytosis with VPS13A mutations remains speculative.

Acta Neuropathol 2009 Jan 26;117(1):95-6; author reply 97-8. Epub 2008 Jul 26.

Neurologische Klinik und Poliklinik, Ludwig-Maximilians-Universität München, Munich, Germany.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00401-008-0418-7DOI Listing
January 2009

Severe hypoxia and multiple infarctions resembling Creutzfeldt-Jakob disease.

Folia Neuropathol 2008 ;46(2):149-53

Institute of Brain Research, University of Tuebingen, Germany.

Although neuropathological examination is still required for the definite diagnosis of Creutzfeldt-Jakob disease (CJD), specialised clinical assessment predicts probable CJD. Here we present a 73-year-old female patient presenting with rapid cognitive decline, visual, acoustic and cerebellar disturbances, ataxia and EEG changes compatible with early CJD stages. MRI revealed hyperintensities within the thalami, hypothalami, corpora mammillaria, the tectum and the cortex. Initial neuropathological examination showed severe cortical and subcortical spongiosis. However, both immunohistochemistry and Western blotting showed no pathological prion protein. Finally, small infarctions affecting the tectum, tegmentum, corpora mammillaria and global hypoxic-ischaemic changes could be identified as the probable reason for the changes interpreted as CJD-related pathology. Hypoxic-ischaemic CNS alterations mainly affecting the supply area of the basilar artery should be ruled out in case of probable CJD. In addition, severe spongiosis can be misleading in the histological examination, suggesting the diagnosis of a prion-induced spongiform encephalopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
August 2008
-->