Patologias neurodegenerativas : o caso particular da doença de Machado-Joseph.

A secção Biologia é coordenada pelo Professor Universitário Armindo Rodrigues.A DMJ é uma doença neurodegenerativa, causada por uma alteração genética transmitida de geração em geração, que atinge nos Açores os seus mais elevados níveis de prevalência

Contributos para o estudo do perfil genético da população da Ilha Graciosa

XI Expedição Científica do Departamento de Biologia - Graciosa 2004.A equipa de Antropologia Biológica tem desenvolvido a sua investigação no sentido de: a) estabelecer o perfil genético das populações açorianas, relacionando a variação obtida com alguns aspectos da estrutura populacional (estudos de genética populacional humana); e b) analisar características particulares que estão envolvidas na dicotomia normal/patológico, estudando a distribuição de patologias genéticas, com o objectivo de perceber os factores que explicam tal distribuição, bem como o seu impacto em termos de Saúde Pública (estudos epidemiológicos)

Machado-Joseph Disease: from first descriptions to new perspectives

Machado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), represents the most common form of SCA worldwide. MJD is an autosomal dominant neurodegenerative disorder of late onset, involving predominantly the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems; although sharing features with other SCAs, the identification of minor, but more specific signs, facilitates its differential diagnosis. MJD presents strong phenotypic heterogeneity, which has justified the classification of patients into three main clinical types. Main pathological lesions are observed in the spinocerebellar system, as well as in the cerebellar dentate nucleus. MJD's causative mutation consists in an expansion of an unstable CAG tract in exon 10 of the ATXN3 gene, located at 14q32.1. Haplotype-based studies have suggested that two main founder mutations may explain the present global distribution of the disease; the ancestral haplotype is of Asian origin, and has an estimated age of around 5,800 years, while the second mutational event has occurred about 1,400 years ago. The ATXN3 gene encodes for ataxin-3, which is ubiquitously expressed in neuronal and non-neuronal tissues, and, among other functions, is thought to participate in cellular protein quality control pathways. Mutated ATXN3 alleles consensually present about 61 to 87 CAG repeats, resulting in an expanded polyglutamine tract in ataxin-3. This altered protein gains a neurotoxic function, through yet unclear mechanisms. Clinical variability of MJD is only partially explained by the size of the CAG tract, which leaves a residual variance that should be explained by still unknown additional factors. Several genetic tests are available for MJD, and Genetic Counseling Programs have been created to better assist the affected families, namely on what concerns the possibility of pre-symptomatic testing. The main goal of this review was to bring together updated knowledge on MJD, covering several aspects from its initial descriptions and clinical presentation, through the discovery of the causative mutation, its origin and dispersion, as well as molecular genetics aspects considered essential for a better understanding of its neuropathology. Issues related with molecular testing and Genetic Counseling, as well as recent progresses and perspectives on genetic therapy, are also addressed

Doença de Machado-Joseph na ilha do Pico (Açores)

XII Expedição Científica do Departamento de Biologia - Pico 2005.A doença de Machado-Joseph (DMJ) é uma doença neurodegenerativa, de transmissão autossómica dominante e de início tardio (média de 40 anos) (Coutinho, 1992), causada pela expansão do tripleto CAG, num gene localizado em 14q32.1 (Kawaguchi et al., 1994). A DMJ constitui nos Açores, dada a sua elevada prevalência, um problema de Saúde Pública. As famílias afectadas dos Açores são originárias das ilhas das Flores, S. Miguel, Terceira e Graciosa, sendo nas ilhas das Flores (1 em cada 106 habitantes é doente) e em S. Miguel (1 em cada 3148 é doente) que se encontra a maior concentração de doentes (Lima et al., 1997). Existem, contudo elementos das referidas famílias em praticamente todas as ihas açorianas, nomeadamente na ilha do Pico. Um conhecimento detalhado da epidemiologia da DMJ nos Açores assume a maior importância, por permitir uma melhor intervenção assistencial, que inclui não só o apoio aos doentes, como se estende aos indivíduos em risco (filhos de um doente DMJ), através da disponibilização do Programa de Aconselhamento Genético e Teste Preditivo

Epigenetic Age Acceleration in Frontotemporal Lobar Degeneration: A Comprehensive Analysis in the Blood and Brain

Frontotemporal lobar degeneration (FTLD) includes a heterogeneous group of disorders pathologically characterized by the degeneration of the frontal and temporal lobes. In addition to major genetic contributors of FTLD such as mutations in MAPT, GRN, and C9orf72, recent work has identified several epigenetic modifications including significant differential DNA methylation in DLX1, and OTUD4 loci. As aging remains one of the major risk factors for FTLD, we investigated the presence of accelerated epigenetic aging in FTLD compared to controls. We calculated epigenetic age in both peripheral blood and brain tissues of multiple FTLD subtypes using several DNA methylation clocks, i.e., DNAmClockMulti, DNAmClockHannum, DNAmClockCortical, GrimAge, and PhenoAge, and determined age acceleration and its association with different cellular proportions and clinical traits. Significant epigenetic age acceleration was observed in the peripheral blood of both frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) patients compared to controls with DNAmClockHannum, even after accounting for confounding factors. A similar trend was observed with both DNAmClockMulti and DNAmClockCortical in post-mortem frontal cortex tissue of PSP patients and in FTLD cases harboring GRN mutations. Our findings support that increased epigenetic age acceleration in the peripheral blood could be an indicator for PSP and to a smaller extent, FTD

Epigenetic age acceleration is associated with oligodendrocyte proportions in MSA and control brain tissue

Aims: Epigenetic clocks are widely applied as surrogates for biological age in different tissues and/or diseases, including several neurodegenerative diseases. Despite white matter (WM) changes often being observed in neurodegenerative diseases, no study has investigated epigenetic ageing in white matter. Methods: We analysed the performances of two DNA methylation-based clocks, DNAmClockMulti and DNAmClockCortical, in post-mortem WM tissue from multiple subcortical regions and the cerebellum, and in oligodendrocyte-enriched nuclei. We also examined epigenetic ageing in control and multiple system atrophy (MSA) (WM and mixed WM and grey matter), as MSA is a neurodegenerative disease comprising pronounced WM changes and α-synuclein aggregates in oligodendrocytes. Results: Estimated DNA methylation (DNAm) ages showed strong correlations with chronological ages, even in WM (e.g., DNAmClockCortical, r = [0.80–0.97], p  0.31, p < 0.05), and similar trends were obtained with DNAmClockMulti. Although increased age acceleration was observed in MSA compared with controls, no significant differences were detected upon adjustment for possible confounders (e.g., cell-type proportions). Conclusions: Our findings show that oligodendrocyte proportions positively influence epigenetic age acceleration across brain regions and highlight the need to further investigate this in ageing and neurodegeneration

Cientistas de palmo e meio: Uma brincadeira muito séria

À semelhança do que acontece noutros países a promoção da cultura científica tem sido uma preocupação em Portugal, em particular na última década. A nossa participação, ao longo de 10 anos, em projectos que visam a introdução do estudo experimental da ciência e tecnologia no ensino pré-escolar e 1.º ciclo do ensino básico permitiu-nos reflectir com um grande número de professores sobre o significado do ensino experimental da ciência e tecnologia nestes graus de ensino, adquirir experiência neste domínio e recolher inúmeros testemunhos de professores e crianças. É desta experiência que damos conta neste artigo. No mundo em que vivemos a cultura científica tem que estar presente na escola se se pretende formar cidadãos intervenientes, esclarecidos, responsáveis e com competências profissionais adaptadas à realidade. Sendo a escolaridade obrigatória de apenas 9 anos, e dado que é neste período que a generalidade das pessoas vai adquirir a sua formação científica básica, é importante que esta comece tão cedo quanto possível. Um longo caminho há ainda a percorrer para se alcançar uma integração efectiva e generalizada do ensino experimental da ciência e tecnologia no pré-escolar e 1.º ciclo do ensino básico em Portugal. Para que se consiga alcançar este objectivo consideramos fundamental o investimento num extenso e profundo processo de formação de professores.As in many other countries, the promotion of scientific culture has been a major concern in Portugal, particularly during the last decade. Our involvement with and participation in several projects that, in the past ten years, have aimed to introduce the experimental study of science and technology in pre-school and primary education has made it possible for us to discuss its meaning and relevance with a vast number of teachers, gain experience in this area and collect teachers’ and pupils’ opinions of and attitudes towards this particular way of teaching / learning science and technology. This experience is discussed in this article. Scientific culture must be present in schools and pupils must engage actively with it in order to become responsible, conscious and involved citizens, with adequate and relevant professional skills. Considering that compulsory education is only nine years long and that it is during this period that basic scientific knowledge is acquired, the experimental study of science and technology must begin as early as possible. The effective and generalized integration of the experimental study of science and technology in pre-school and primary education in Portugal is far from complete and it will only be achieved through the development of and investment in an extensive and thorough process of teacher training.info:eu-repo/semantics/publishedVersio

Cientistas de palmo e meio: Uma brincadeira muito séria

À semelhança do que acontece noutros países a promoção da cultura científica tem sido uma preocupação em Portugal, em particular na última década. A nossa participação, ao longo de 10 anos, em projectos que visam a introdução do estudo experimental da ciência e tecnologia no ensino pré-escolar e 1.º ciclo do ensino básico permitiu-nos reflectir com um grande número de professores sobre o significado do ensino experimental da ciência e tecnologia nestes graus de ensino, adquirir experiência neste domínio e recolher inúmeros testemunhos de professores e crianças. É desta experiência que damos conta neste artigo. No mundo em que vivemos a cultura científica tem que estar presente na escola se se pretende formar cidadãos intervenientes, esclarecidos, responsáveis e com competências profissionais adaptadas à realidade.Sendo a escolaridade obrigatória de apenas 9 anos, e dado que é neste período que a generalidade das pessoas vai adquirir a sua formação científica básica, é importante que esta comece tão cedo quanto possível. Um longo caminho há ainda a percorrer para se alcançar uma integração efectiva e generalizada do ensino experimental da ciência e tecnologia no pré-escolar e 1.º ciclo do ensino básico em Portugal. Para que se consiga alcançar este objectivo consideramos fundamental o investimento num extenso e profundo processo de formação de professores

Novel candidate blood-based transcriptional biomarkers of Machado-Joseph disease

BACKGROUND: Machado-Joseph disease (or spinocerebellar ataxia type 3) is a late-onset polyglutamine neurodegenerative disorder caused by a mutation in the ATXN3 gene, which encodes for the ubiquitously expressed protein ataxin-3. Previous studies on cell and animal models have suggested that mutated ataxin-3 is involved in transcriptional dysregulation. Starting with a whole-transcriptome profiling of peripheral blood samples from patients and controls, we aimed to confirm abnormal expression profiles in Machado-Joseph disease and to identify promising up-regulated genes as potential candidate biomarkers of disease status. METHODS: The Illumina Human V4-HT12 array was used to measure transcriptome-wide gene expression in peripheral blood samples from 12 patients and 12 controls. Technical validation and validation in an independent set of samples were performed by quantitative real-time polymerase chain reaction (PCR). RESULTS: Based on the results from the microarray, twenty six genes, found to be up-regulated in patients, were selected for technical validation by quantitative real-time PCR (validation rate of 81% for the up-regulation trend). Fourteen of these were further tested in an independent set of 42 patients and 35 controls; 10 genes maintained the up-regulation trend (FCGR3B, CSR2RA, CLC, TNFSF14, SLA, P2RY13, FPR2, SELPLG, YIPF6, and GPR96); FCGR3B, P2RY13, and SELPLG were significantly up-regulated in patients when compared with controls. CONCLUSIONS: Our findings support the hypothesis that mutated ataxin-3 is associated with transcription dysregulation, detectable in peripheral blood cells. Furthermore, this is the first report suggesting a pool of up-regulated genes in Machado-Joseph disease that may have the potential to be used for fine phenotyping of this disease.Fundação para a Ciência e a Tecnologia (FCT) - project FCOMP-01-0124-FEDER-028753 (PTDC/DTP/PIC/0370/2012)Operational Competitiveness Programme—COMPETEUK Medical Research Council (MRC)Fundação para a Ciência e a Tecnologia (FCT) - SFRH/BPD/33611/2009Fundo Regional para a Ciência (FRC), Governo dos Açores - M3.1.2/F/006/2011; M3.1.7/F/031/2011 ; M3.1.3/F/004/200

Patterns of mitochondrial DNA damage in blood and brain tissues of a transgenic mouse model of Machado-Joseph disease

BACKGROUND: Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar ataxia caused by a CAG tract expansions in the ATXN3 gene. Patterns of mitochondrial damage associated with pathological findings of brain tissues could provide molecular biomarkers of this disorder. OBJECTIVE: The potential of mitochondrial DNA (mtDNA) damage as a biomarker of MJD progression was investigated using a transgenic mouse model. METHODS: DNA was obtained from affected (pontine nuclei) and nonaffected tissues (hippocampus and blood) of transgenic animals of three distinct age groups: 8 weeks, before onset of the phenotype; 16 weeks, at onset, and 24 weeks, at well-established phenotype. Wild-type littermate mice, serving as controls, were analyzed for the same tissues and age groups. mtDNA damage was studied by fluorescence-based quantitative PCR in 84 transgenic and 93 wild-type samples. RESULTS: A clear pattern of decrease in mtDNA copy number with age and accumulation of 3,867-bp deletions at the initial stages (both being more pronounced in transgenic mice) was observed. Pontine nuclei, the affected tissue in transgenic mice, displayed 1.5 times less copies of mtDNA than nonaffected brain tissue hippocampus (odds ratio = 1.21). Pontine nuclei displayed the highest percentage of mtDNA deletions (6.05% more in transgenic mice). CONCLUSION: These results suggest that mtDNA damage is related to the initiation of the phenotype in transgenic mice; mtDNA 3,867-bp deletions may be a biomarker of the initial stages of the disease.This study was supported by the following grants: DRCT Postdoctoral fellowship to N.K. (M3.1.7/F/002/2008), FCT Postdoctoral fellowship to T.C. (SFRH/BPD/38659/2007) and C.B. (SFRH/BPD/63121/2009), FCT research grants to S.S. (PTDC/SAU-GMG/64076/2006) and A.S.F. (PIC/IC/83013/2007)