News
February
α-synuclein phosphorylation and truncation are normal events in the adult human brain. Muntané G, Ferrer I, Martinez-Vicente M. Neuroscience 2012; 200:106-19.
Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL-Hospital Universitari de Bellvitge, Hospitalet de LLobregat, CIBERNED, Instituto Carlos III, Barcelona, Spain.
α-synuclein is a key protein in Lewy body diseases (LBDs) and a major component of Lewy bodies and related aberrant cytoplasmic and neuritic inclusions. Regional differences in α-synuclein have been associated with selective neuronal vulnerability to Lewy pathology. Furthermore, phosphorylation at serine 129 (Ser129) and α-synuclein truncation have been considered crucial in the pathogenesis of Lewy inclusions. The present study shows consistent reduction in α-synuclein protein expression levels in the human substantia nigra and nucleus basalis of Meynert compared with other brain regions independently of age and pathology. Phosphorylated α-synuclein at Ser129 is naturally increased in these same regions, thus inversely related with the total amount of α-synuclein. In contrast, truncated α-synuclein is naturally observed in control and diseased brains and correlating with the total amount of α-synuclein. Several truncated variants have been identified where some of these variants are truncated at the C-terminal domain, whereas others are truncated at the N-terminal domain, and all are present in cases with and without Lewy pathology. Although accumulation of truncated α-synuclein variants and phosphorylated α-synuclein occurs in Lewy bodies, α-synuclein phosphorylation and truncation can be considered constitutive in control and diseased brains
New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases. Beyer K, Munoz-Marmol AM, Sanz C, Marginet-Flinch R, Ferrer I, Ariza A. Neurogenetics. 2011 Dec 29
Servicio de Anatomía Patológica, Hospital Universitario Germans Trias i Pujol, Ctra Canyet s/n, 08916, Badalona, Barcelona, Spain
Lewy body diseases (LBDs) include dementia with Lewy bodies (DLB) and Parkinson disease (PD). Alpha-synuclein (AS) aggregation is a key event in the pathogenesis of LBDs and beta-synuclein (BS) inhibits AS aggregation in vitro and in vivo. Recently, BS has been shown to interact directly with AS regulating its functionality and preventing its oligomerization, and a molecular subgroup of pure DLB lacks BS in cortical regions. In this study, we characterized four new BS transcript variants and analyzed their expression in neuronal and non-neuronal tissue, and their differential expression in frozen samples of three areas from brains of patients with pure Lewy body pathology (LBP), common LBP, Alzheimer pathology, and of controls. Relative mRNA expression was determined by real-time PCR with neuron-specific enolase 2 and synaptophysin as housekeeping genes, and expression changes were evaluated by the ΔΔCt method. Two main findings are in concordance with earlier studies. First, all BS isoforms are drastically diminished in the cortex of patients with pure LBP that had presented clinically as DLB but not PD with dementia. Second, an important shift of the isoform expression ratio was observed in the temporal cortex of all LBD cases, and the minor isoforms, normally absent in the midbrain, were detected in the caudate nucleus of all DLB samples. Our results provide further evidence for the role of minor transcript variants in the development of complex diseases and provide new insights into the pathogenesis of LBDs that may be important for the understanding of molecular mechanisms involved in these complex diseases
Amyloid Generation and Dysfunctional Immunoproteasome Activation with Disease Progression in Animal Model of Familial Alzheimer's Disease. Aso E, Lomoio S, López-González I, Joda L, Carmona M, Fernández-Yagüe N, Moreno J, Juvés S, Pujol A, Pamplona R, Portero-Otin M, Martín V, Díaz M, Ferrer I. Brain Pathol. 2011 Dec 20
Institut de Neuropatologia, IDIBELL-Hospital Universitari de Bellvitge, Universitat de Barcelona, Hospitalet de Llobregat; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain Dipartimento di Biologia Animale, Laboratorio di Biologia Cellulare e Neurobiologia, Università di Pavia, Pavia, Italy Catalan Institution of Research and Advanced Studies (ICREA), Centre de Genètica Mèdica i Molecular, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain Departament de Medicina Experimental, Universitat de Lleida-IRBLleida, Lleida, Spain Laboratorio de Fisiología y Biofísica de Membranas, Departamento de Biología Animal e Instituto de Tecnologías Biomédicas, Universidad de La Laguna, Tenerife, Spain.
Double-transgenic amyloid precursor protein/presenilin 1 (APP/PS1) mice express a chimeric mouse/human APP bearing the Swedish mutation (Mo/HuAPP695swe) and a mutant human PS1-dE9 both causative of familial Alzheimer's disease (FAD). Transgenic mice show impaired memory and learning performance from the age of 6 months onwards. Double-transgenic APP/PS1 mice express altered APP and PS1 mRNAs and proteins, reduced β-secretase 1 (BACE1) mRNA and normal BACE1 protein, all of which suggest a particular mechanism of amyloidogenesis when compared with sporadic AD. The first β-amyloid plaques in APP/PS1 mice appear at 3 months, and they increase in number and distribution with disease progression in parallel with increased levels of brain soluble β-amyloid 1-42 and 1-40, but also with reduced 1-42/1-40 ratio with age. Amyloid deposition in plaques is accompanied by altered mitochondria and increased oxidative damage, post-translational modifications and accumulation of altered proteins at the dystrophic neurites surrounding plaques. Degradation pathways are also modified with disease progression including activation of the immunoproteasome together with variable alterations of the different protease activities of the ubiquitin-proteasome system. Present observations show modifications in the production of β-amyloid and activation and malfunction of the subcellular degradation pathways that have general implications in the pathogenesis of AD and more particularly in specificities of FAD amyloidogenesis.
α-Synuclein accumulates in huntingtin inclusions but forms independent filaments and its deficiency attenuates early phenotype in a mouse model of Huntington's disease. Tomás-Zapico C, Díez-Zaera M, Ferrer I, Gómez-Ramos P, Morán MA, Miras-Portugal MT, Díaz-Hernández M, Lucas JJ. Hum Mol Genet. 2011 Nov 14
Center for Molecular Biology 'Severo Ochoa' (CBMSO), CSIC/UAM, Madrid, Spain.
Huntington's disease (HD) is the most common of nine inherited neurological disorders caused by expanded polyglutamine (polyQ) sequences which confer propensity to self-aggregate and toxicity to their corresponding mutant proteins. It has been postulated that polyQ expression compromises the folding capacity of the cell which might affect other misfolding-prone proteins. α-Synuclein (α-syn) is a small neural-specific protein with propensity to self-aggregate that forms Parkinson's disease (PD) Lewy bodies. Point mutations in α-syn that favor self-aggregation or α-syn gene duplications lead to familial PD, thus indicating that increased α-syn aggregation or levels are sufficient to induce neurodegeneration. Since polyQ inclusions in HD and other polyQ disorders are immunopositive for α-syn, we speculated that α-syn might be recruited as an additional mediator of polyQ toxicity. Here, we confirm in HD postmortem brains and in the R6/1 mouse model of HD the accumulation of α-syn in polyQ inclusions. By isolating the characteristic filaments formed by aggregation-prone proteins, we found that N-terminal mutant huntingtin (N-mutHtt) and α-syn form independent filamentous microaggregates in R6/1 mouse brain as well as in the inducible HD94 mouse model and that N-mutHtt expression increases the load of α-syn filaments. Accordingly, α-syn knockout results in a diminished number of N-mutHtt inclusions in transfected neurons and also in vivo in the brain of HD mice. Finally, α-syn knockout attenuates body weight loss and early motor phenotype of HD mice. This study therefore demonstrates that α-syn is a modifier of polyQ toxicity in vivo and raises the possibility that potential PD-related therapies aimed to counteract α-syn toxicity might help to slow HD.
Histone tail acetylation in brain occurs in an unpredictable fashion after death. Barrachina M, Moreno J, Villar-Menéndez I, Juvés S, Ferrer I. Cell Tissue Bank. 2011 Sep 16
Institute of Neuropathology, [Bellvitge Biomedical Research Institute-] IDIBELL, Bellvitge University Hospital-ICS, c/Feixa Llarga s/n, 08908, L'Hospitalet de Llobregat, Spain
Histone acetylation plays a role in the regulation of gene transcription. Yet it is not known whether post-mortem brain tissue is suitable for the analysis of histone acetylation. To examine this question, nucleosomes were isolated from frontal cortex of nine subjects which were obtained at short times after death and immediately frozen at -80°C or maintained at room temperature from 3 h up to 50 h after death and then frozen at -80°C to mimic variable post-mortem delay in tissue processing as currently occurs in normal practice. Chromatin immunoprecipitation assays were performed for two lysine residues, H3K9ac and H3K27ac. Four gene loci were amplified by SyBrGreen PCR: Adenosine A(2A) receptor, UCHL1, α-synuclein and β-globin. Results showed variability in the histone acetylation level along the post-mortem times and an increase in the acetylation level at an unpredictable time from one case to another and from one gene to another within the first 24 h of post-mortem delay. Similar results were found with three rat brains used to exclude the effects of agonal state and to normalize the start-point as real time zero. Therefore, the present observations show that human post-mortem brain is probably not suitable for comparative studies of histone acetylation
Hirano body - rich subtypes of Creutzfeldt-Jakob disease. Martinez-Saez E, Gelpi E, Rey M, Ferrer I, Ribalta T, Botta-Orfila T, Nos C, Yagüe J, Sanchez-Valle R. Neuropathol Appl Neurobiol. 2011 Jul 5
Neurological Tissue Bank University of Barcelona SCT - Hospital Clínic - IDIBAPS; Vall d'Hebron Research Institute and Pathology Department; Institut de Neuropatologia, Hospital Universitari de Bellvitge; Pathology Department, CJD Unit, Parkinson`s Disease and Movement Disorders Unit, and Alzheimer disease and other cognitive disorders Unit, Hospital Clínic, General Subdirectorate of Surveillance and Response to Emergencies in Public Health, Department of Public Health in Catalonia; Barcelona, Spain.
Background. In definite Creutzfeldt-Jakob disease, morphological and immunohistochemical patterns are useful to identify molecular subtypes. Severe cerebellar pathology and hippocampal involvement helps to identify VV subtypes. The rare VV1 variant (<1%), more frequent in young individuals, is additionally characterised by the presence of ballooned neurons in affected areas. In 1985 Cartier et al. described a family cluster of 3 individuals with an ataxic CJD form, showing, in addition to severe cerebellar and hippocampal involvement, the presence of frequent Hirano bodies (HB) in CA1 pyramidal neurons. HB are frequently found in aged individuals with Alzheimer pathology although they are not a specific finding. Aims and methods. In this study we evaluated the presence of HB in hippocampi of 54 genetically and molecularly characterized CJD cases, aiming to elucidate whether additional morphological features could be helpful to point to molecular subtypes. Results. We identified 9 cases (4 VV1, 1 out of 3 MV2K, 3 out of 6 MV2K+2C, and one MV carrying a 96 bpi) with abundant, partly bizarre and clustered HB in CA1-sector, not observed in other subtypes. The presence of HB was independent of hippocampal involvement by the disease itself. Conclusions. Clusters of abundant HB might be found in rare CJD subtypes such as VV1, MV2K/MV2K+2C, and some genetic cases. In addition to histopathological and PrP immunohistochemical deposition patterns, their presence might be a useful additional morphologic feature that could point to the molecular subtype, especially when genetic and/or WB analyses are not available.
“Preclinical" MSA in definite Creutzfeldt-Jakob disease. Neuropathology. Rodriguez-Diehl R, Rey MJ, Gironell A, Martinez-Saez E, Ferrer I, Sánchez-Valle R, Jagüe J, Nos C, Gelpi E. 2011 Jun 21
Neurological Tissue Bank, University of Barcelona SCT - Hospital Clínic Department of Neurology, Hospital de Sant Pau Vall d'Hebrón Research Institute and Pathology Department Institut de Neuropatologia, Hospital Universitari de Bellvitge CJD Unit Alzheimer Disease and Other Cognitive Disorders Unit, Hospital Clínic General Subdirectorate of Surveillance and Response to Emergencies in Public Health, Department of Public Health in Catalonia, Barcelona, Spain Department of Neurology, Santa Casa Hospital Complex, UFSCPA, Porto Alegre, Brazil.
Multiple system atrophy (MSA) is a sporadic alpha-synucleinopathy clinically characterized by variable degrees of parkinsonism, cerebellar ataxia and autonomic dysfunction. The histopathological hallmark of MSA is glial cytoplasmic inclusion (GCI). It is considered to represent the earliest stage of the degenerative process in MSA and to precede neuronal degeneration. Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal, rapidly progressive dementia generally associated with ataxia, pyramidal and extrapyramidal symptoms and myoclonus. Definite diagnosis needs neuropathological demonstration of variable degrees of spongiform degeneration of neuropil, neuronal loss, astro- and microgliosis, and the presence of abnormal deposits of the misfolded prion protein PrP(res) . Both diseases, CJD and MSA are infrequent among neurodegenerative diseases. In the present report we describe clinical and neuropathological findings of a previously healthy 64-year-old woman who developed symptoms of classical CJD. At post mortem examination, the brain showed in addition to classical methionine/methionine PrP(res) type 1 (MM1) sCJD changes and moderate Alzheimer-type pathology, features of "preclinical" MSA with minimal histopathological changes. These were characterized by discrete amounts of alpha-synuclein immunoreacive glial cytoplasmic inclusions in the striato-nigral system, isolated intraneuronal inclusions in pigmented neurons of the substantia nigra, as well as some vermiform intranuclear inclusions. To our knowledge, this is the first report on the coexistence of definite sCJD and "minimal changes" MSA in the same patient.
Isolated cardiomyopathy caused by a DMD nonsense mutation in somatic mosaicism: genetic normalization in skeletal muscle. Juan-Mateu J, Paradas C, Olivé M, Verdura E, Rivas E, González-Quereda L, Rodríguez MJ, Baiget M, Gallano P. Clin Genet 2011 Nov 17
Genetics Department, Hospital Sant Pau, CIBERER, Barcelona, Spain Universitat de Barcelona (UB), Barcelona, Spain Neurology Department, Hospital Virgen del Rocío/IBiS/CIBERNED, Sevilla, Spain Institut de Neuropatologia, IDIBELL-Hospital de Bellvitge, CIBERNED, Hospitalet de Llobregat, L'Hospitalet de Llobregat, Spain Pathology Department, Hospital Virgen del Rocío, Sevilla, Spain.
X-linked dilated cardiomyopathy is a pure cardiac dystrophinopathy phenotype mainly caused by DMD mutations that present a specific transcription effect in cardiac tissue. We report a 26-year-old male who presented with severe dilated cardiomyopathy and high creatine kinase. The patient did not complain of skeletal muscle weakness. A muscle biopsy showed mild dystrophic changes and a low proportion of dystrophin-negative fibres. A molecular study identified a nonsense DMD mutation (p.Arg2098X) in somatic mosaicism. The ratio of mutant versus normal allele in blood and skeletal muscle suggests selective pressure against mutant muscle cells, a process known as genetic normalization. We hypothesize that this process may have mitigated skeletal muscle symptoms in this patient. This is the second report of a DMD somatic mosaic with evidence of genetic normalization in muscle. Somatic DMD mutations should be considered in patients presenting with idiopathic dilated cardiomyopathy.
