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1.
J Neurol Neurosurg Psychiatry ; 91(2): 162-171, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31690696

RESUMO

OBJECTIVE: Since the first report of CHCHD10 gene mutations in amyotrophiclateral sclerosis (ALS)/frontotemporaldementia (FTD) patients, genetic variation in CHCHD10 has been inconsistently linked to disease. A pathological assessment of the CHCHD10 protein in patient neuronal tissue also remains to be reported. We sought to characterise the genetic and pathological contribution of CHCHD10 to ALS/FTD in Australia. METHODS: Whole-exome and whole-genome sequencing data from 81 familial and 635 sporadic ALS, and 108 sporadic FTD cases, were assessed for genetic variation in CHCHD10. CHCHD10 protein expression was characterised by immunohistochemistry, immunofluorescence and western blotting in control, ALS and/or FTD postmortem tissues and further in a transgenic mouse model of TAR DNA-binding protein 43 (TDP-43) pathology. RESULTS: No causal, novel or disease-associated variants in CHCHD10 were identified in Australian ALS and/or FTD patients. In human brain and spinal cord tissues, CHCHD10 was specifically expressed in neurons. A significant decrease in CHCHD10 protein level was observed in ALS patient spinal cord and FTD patient frontal cortex. In a TDP-43 mouse model with a regulatable nuclear localisation signal (rNLS TDP-43 mouse), CHCHD10 protein levels were unaltered at disease onset and early in disease, but were significantly decreased in cortex in mid-stage disease. CONCLUSIONS: Genetic variation in CHCHD10 is not a common cause of ALS/FTD in Australia. However, we showed that in humans, CHCHD10 may play a neuron-specific role and a loss of CHCHD10 function may be linked to ALS and/or FTD. Our data from the rNLS TDP-43 transgenic mice suggest that a decrease in CHCHD10 levels is a late event in aberrant TDP-43-induced ALS/FTD pathogenesis.


Assuntos
Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Proteínas Mitocondriais/genética , Idoso , Esclerose Lateral Amiotrófica/imunologia , Esclerose Lateral Amiotrófica/patologia , Animais , Austrália , Western Blotting , Encéfalo/patologia , Feminino , Imunofluorescência , Demência Frontotemporal/imunologia , Demência Frontotemporal/patologia , Variação Genética/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Córtex Motor/patologia , Medula Espinal/patologia , Sequenciamento do Exoma , Sequenciamento Completo do Genoma
2.
Brain ; 138(Pt 10): 3110-22, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26231953

RESUMO

The pathological sequestration of TAR DNA-binding protein 43 (TDP-43, encoded by TARDBP) into cytoplasmic pathological inclusions characterizes the distinct clinical syndromes of amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia, while also co-occurring in a proportion of patients with Alzheimer's disease, suggesting that the regional concentration of TDP-43 pathology has most relevance to specific clinical phenotypes. This has been reflected in the three different pathological staging schemes for TDP-43 pathology in these different clinical syndromes, with none of these staging schemes including a preclinical phase similar to that which has proven beneficial in other neurodegenerative diseases. To apply each of these three staging schemes for TDP-43 pathology, the clinical phenotype must be known undermining the potential predictive value of the pathological examination. The present study set out to test whether a more unified approach could accurately predict clinical phenotypes based solely on the regional presence and severity of TDP-43 pathology. The selection of brain regions of interest was based on key regions routinely sampled for neuropathological assessment under current consensus criteria that have also been used in the three TDP-43 staging schemes. The severity of TDP-43 pathology in these regions of interest was assessed in four clinicopathological phenotypes: amyotrophic lateral sclerosis (n = 27, 47-78 years, 15 males), behavioural variant frontotemporal dementia (n = 15, 49-82 years, seven males), Alzheimer's disease (n = 26, 51-90 years, 11 males) and cognitively normal elderly individuals (n = 17, 80-103 years, nine males). Our results demonstrate that the presence of TDP-43 in the hypoglossal nucleus discriminates patients with amyotrophic lateral sclerosis with an accuracy of 98%. The severity of TDP-43 deposited in the anterior cingulate cortex identifies patients with behavioural variant frontotemporal dementia with an accuracy of 99%. This identification of regional pathology associated with distinct clinical phenotypes suggests key regions on which probabilistic pathological criteria, similar to those currently available for Alzheimer's disease and dementia with Lewy bodies, can be developed for TDP-43 proteinopathies. We propose and validate a simplified probabilistic statement that involves grading the presence of TDP-43 in the hypoglossal nucleus and the severity of TDP-43 in the anterior cingulate for the pathological identification of TDP-43 proteinopathy cases with clinical amyotrophic lateral sclerosis and behavioural variant frontotemporal dementia.


Assuntos
Encéfalo/patologia , Proteínas de Ligação a DNA/metabolismo , Fenótipo , Proteinopatias TDP-43/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/patologia , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
3.
Lancet ; 383(9919): 828-40, 2014 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23927914

RESUMO

25% of all people aged 55 years and older have a family history of dementia. For most, the family history is due to genetically complex disease, where many genetic variations of small effect interact to increase risk of dementia. The lifetime risk of dementia for these families is about 20%, compared with 10% in the general population. A small proportion of families have an autosomal dominant family history of early-onset dementia, which is often due to mendelian disease, caused by a mutation in one of the dementia genes. Each family member has a 50% chance of inheriting the mutation, which confers a lifetime dementia risk of over 95%. In this Review, we focus on the evidence for, and the approach to, genetic testing in Alzheimer's disease (APP, PSEN1, and PSEN2 genes), frontotemporal dementia (MAPT, GRN, C9ORF72, and other genes), and other familial dementias. We conclude by discussing the practical aspects of genetic counselling.


Assuntos
Demência/genética , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Demência/diagnóstico , Aconselhamento Genético/métodos , Ligação Genética/genética , Testes Genéticos , Variação Genética/genética , Humanos , Pessoa de Meia-Idade , Mutação/genética , Linhagem , Fenótipo
4.
Acta Neuropathol ; 127(3): 407-18, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24442578

RESUMO

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease.


Assuntos
Degeneração Lobar Frontotemporal/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Proteínas/genética , Adulto , Fatores Etários , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Alelos , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/mortalidade , Proteína C9orf72 , Estudos de Coortes , Expansão das Repetições de DNA , Feminino , Degeneração Lobar Frontotemporal/sangue , Degeneração Lobar Frontotemporal/mortalidade , Predisposição Genética para Doença , Genótipo , Heterozigoto , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Progranulinas
5.
Mov Disord ; 29(13): 1606-14, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24375821

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder for which environmental factors influence disease risk and may act via an epigenetic mechanism. The microtubule-associated protein tau (MAPT) is a susceptibility gene for idiopathic PD. Methylation levels were determined by pyrosequencing of bisulfite-treated DNA in a leukocyte cohort (358 PD patients and 1084 controls) and in two brain cohorts (Brain1, comprising 69 cerebellum controls; and Brain2, comprising 3 brain regions from 28 PD patients and 12 controls). In vitro assays involved the transfection of methylated promoter-luciferase constructs or treatment with an exogenous micronutrient. In normal leukocytes, the MAPT H1/H2 diplotype and sex were predictors of MAPT methylation. Haplotype-specific pyrosequencing confirmed that the H1 haplotype had higher methylation than the H2 haplotype in normal leukocytes and brain tissues. MAPT methylation was negatively associated with MAPT expression in the Brain1 cohort and in transfected cells. Methylation levels differed between three normal brain regions (Brain2 cohort, putamen < cerebellum < anterior cingulate cortex). In PD samples, age at onset was positively associated with MAPT methylation in leukocytes. Moreover, there was hypermethylation in the cerebellum and hypomethylation in the putamen of PD patients compared with controls (Brain2 cohort). Finally, leukocyte methylation status was positively associated with blood vitamin E levels, and the effect was more significant in H2 haplotype carriers; this result was confirmed in cells that were exposed to 100 µM vitamin E. The significant effects of sex, diplotype, and brain region suggest that hypermethylation of the MAPT gene is neuroprotective by reducing MAPT expression. The effect of vitamin E on MAPT represents a possible gene-environment interaction.


Assuntos
Antioxidantes/farmacologia , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Doença de Parkinson/genética , Vitamina E/farmacologia , Proteínas tau/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Linhagem Celular Tumoral , Estudos de Coortes , Feminino , Genótipo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Neuroblastoma/patologia , Doença de Parkinson/patologia , Regiões Promotoras Genéticas , Transfecção
6.
Acta Neuropathol ; 125(4): 523-33, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23338750

RESUMO

Numerous families exhibiting both frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) have been described, and although many of these have been shown to harbour a repeat expansion in C9ORF72, several C9ORF72-negative FTD-ALS families remain. We performed neuropathological and genetic analysis of a large European Australian kindred (Aus-12) with autosomal dominant inheritance of dementia and/or ALS. Affected Aus-12 members developed either ALS or dementia; some of those with dementia also had ALS and/or extrapyramidal features. Neuropathology was most consistent with frontotemporal lobar degeneration with type B TDP pathology, but with additional phosphorylated tau pathology consistent with corticobasal degeneration. Aus-12 DNA samples were negative for mutations in all known dementia and ALS genes, including C9ORF72 and FUS. Genome-wide linkage analysis provided highly suggestive evidence (maximum multipoint LOD score of 2.9) of a locus on chromosome 16p12.1-16q12.2. Affected individuals shared a chromosome 16 haplotype flanked by D16S3103 and D16S489, spanning 37.9 Mb, with a smaller suggestive disease haplotype spanning 24.4 Mb defined by recombination in an elderly unaffected individual. Importantly, this smaller region does not overlap with FUS. Whole-exome sequencing identified four variants present in the maximal critical region that segregate with disease. Linkage analysis incorporating these variants generated a maximum multipoint LOD score of 3.0. These results support the identification of a locus on chromosome 16p12.1-16q12.2 responsible for an unusual cluster of neurodegenerative phenotypes. This region overlaps with a separate locus on 16q12.1-q12.2 reported in an independent ALS family, indicating that this region may harbour a second major locus for FTD-ALS.


Assuntos
Esclerose Lateral Amiotrófica/genética , Encéfalo/patologia , Cromossomos Humanos Par 16 , Demência Frontotemporal/genética , Idoso , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Encéfalo/metabolismo , Proteínas de Ligação a DNA/metabolismo , Feminino , Demência Frontotemporal/metabolismo , Demência Frontotemporal/patologia , Ligação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Escore Lod , Masculino , Pessoa de Meia-Idade , Fosforilação , Proteínas tau/metabolismo
7.
J Neurochem ; 123(1): 159-71, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22788679

RESUMO

Previously, we reported elevated levels of the neuron-specific tropomyosin receptor kinase B (TrkB) transcript, TrkB- sarc homology containing (Shc) in the hippocampus of Alzheimer's disease (AD) brains. In this study, we determined how TrkB-Shc transcripts are increased in AD. Utilizing a TrkB minigene transiently transfected into SHSY5Y cells, we found increased exon 19 inclusion in TrkB minigene transcripts (to generate TrkB-Shc) following cellular exposure to amyloid beta 1-42 (Αß(42)). As this suggested altered TrkB pre-mRNA splicing in AD, we conducted an in silico screening for putative splice regulatory protein-binding sites in the intron/exon splice regulatory regions of exons 18 and 19 of the TrkB gene and then assessed their gene expression profiles using a microarray database of control/AD post-mortem human hippocampal brain tissue. We found significant changes in serine/arginine protein 20 (Srp20) gene expression in AD cases and confirmed this using a second cohort of control/AD. In vitro, we found increased Srp20 mRNA levels in SHSY5Y cells treated with Αß(42) fibrils. Moreover, Srp20 over-expression was found to increase exon 19 inclusion in TrkB minigene transcripts and ratio of endogenous TrkB-Shc:TrkB-TK+ mRNA expression. Conversely, Srp20 expression knockdown produced the opposite effects. Our findings suggest that dysregulation of factors regulating TrkB pre-mRNA splicing may contribute to gene expression changes that occur in AD.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/fisiologia , Splicing de RNA/genética , Proteínas de Ligação a RNA/metabolismo , Receptor trkB/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Análise de Variância , Sítios de Ligação/genética , Encéfalo/patologia , Linhagem Celular Tumoral , Éxons/efeitos dos fármacos , Éxons/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Masculino , Análise em Microsséries , Neuroblastoma/patologia , Fragmentos de Peptídeos/farmacologia , Ligação Proteica , Isoformas de Proteínas , Precursores de RNA/genética , Precursores de RNA/metabolismo , Splicing de RNA/efeitos dos fármacos , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Proteínas de Ligação a RNA/genética , Receptor trkB/genética , Fatores de Processamento de Serina-Arginina , Transcriptoma
8.
Mov Disord ; 27(8): 1004-11, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22528366

RESUMO

Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease (PD) and are associated with pleiomorphic neuropathology. We hypothesize that LRRK2 mediates its pathogenic effect through alternative splicing of neurodegeneration genes. Methods used in this study included western blotting analysis of subcellular protein fractions, exon-array analysis of RNA from cultured neuroblastoma cells transfected with LRRK2 expression vectors, and reverse-transcription polymerase chain reaction (RT-PCR) of RNA from cultured cells and postmortem tissue. Overexpression of the LRRK2 G2019S mutant resulted in a significant (2.6-fold; P = 0.020) decrease in nuclear transactive response DNA-binding protein 43 levels. Exon-array analyses revealed that wild-type LRRK2 had a significant effect on the expression of genes with nuclear (P < 10(-22) ) and cell-cycle functions (P < 10(-15) ). We replicated changes in gene expression in 30% of selected genes by quantitative RT-PCR. Overexpression of LRRK2 resulted in the altered splicing of two genes associated with PD, with an increased inclusion of exon 10 of microtubule-associated protein tau (1.7-fold; P = 0.001) and exon 5 of the alpha-synuclein (SNCA) gene (1.6-fold; P =0.005). Moreover, overexpression of LRRK2 (G2019S) and two mutant genes associated with neurodegeneration, TARDBP (M337V) and FUS (R521H), were associated with decreased inclusion out of the dystonin (DST) 1e precursor exons in SK-N-MC cells. Altered splicing of SNCA (1.9-fold; P < 0.001) and DST genes (log(2) 2.3-fold; P = 0.005) was observed in a cohort of PD, compared with neurologically healthy, brains. This suggests that aberrant RNA metabolism is an important contributor to idiopathic PD.


Assuntos
Processamento Alternativo , Doença de Parkinson/genética , Proteínas Serina-Treonina Quinases/genética , Idoso , Idoso de 80 Anos ou mais , Autopsia , DNA Complementar/genética , Proteínas de Ligação a DNA/genética , Éxons/genética , Feminino , Dosagem de Genes , Expressão Gênica/genética , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Masculino , Microdomínios da Membrana/genética , Mutação , Doença de Parkinson/patologia , Reação em Cadeia da Polimerase em Tempo Real , alfa-Sinucleína/genética , Proteínas tau/genética
9.
Ann Neurol ; 68(5): 639-49, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21031579

RESUMO

OBJECTIVE: Frontotemporal lobar degeneration (FTLD) is the most common cause of early-onset dementia. Pathological ubiquitinated inclusion bodies observed in FTLD and motor neuron disease (MND) comprise trans-activating response element (TAR) DNA binding protein (TDP-43) and/or fused in sarcoma (FUS) protein. Our objective was to identify the causative gene in an FTLD-MND pedigree with no mutations in known dementia genes. METHODS: A mutation screen of candidate genes, luciferase assays, and quantitative polymerase chain reaction (PCR) was performed to identify the biological role of the putative mutation. Neuropathological characterization of affected individuals and western blot studies of cell lines were performed to identify the pathological mechanism of the mutation. RESULTS: We identified a nonpolymorphic mutation (c.672*51G>T) in the 3'-untranslated region (UTR) of the Sigma nonopioid intracellular receptor 1 (SIGMAR1) gene in affected individuals from the FTLD-MND pedigree. The c.672*51G>T mutation increased gene expression by 1.4-fold, corresponding with a significant 1.5-fold to 2-fold change in the SIGMAR1 transcript or Sigma-1 protein in lymphocyte or brain tissue. Brains of SIGMAR1 mutation carriers displayed a unique pathology with cytoplasmic inclusions immunopositive for either TDP-43 or FUS but not Sigma-1. Overexpression of SIGMAR1 shunted TDP-43 and FUS from the nucleus to the cytoplasm by 2.3-fold and 5.2-fold, respectively. Treatment of cells with Sigma-1 ligands significantly altered translocation of TDP-43 by up to 2-fold. INTERPRETATION: SIGMAR1 is a causative gene for familial FTLD-MND with a unique neuropathology that differs from other FTLD and MND cases. Our findings also suggest Sigma-1 drugs as potential treatments for the TDP-43/FUS proteinopathies.


Assuntos
Degeneração Lobar Frontotemporal/genética , Doença dos Neurônios Motores/genética , Receptores sigma/genética , Idoso , Idoso de 80 Anos ou mais , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular Transformada , Proteínas de Ligação a DNA/metabolismo , Feminino , Degeneração Lobar Frontotemporal/metabolismo , Degeneração Lobar Frontotemporal/patologia , Haloperidol/farmacologia , Humanos , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Mutação , Opipramol/farmacologia , Linhagem , Fenilacetatos/farmacologia , Pirrolidinas/farmacologia , Proteína FUS de Ligação a RNA/metabolismo , Receptores sigma/agonistas , Receptores sigma/antagonistas & inibidores , Receptores sigma/metabolismo , Receptor Sigma-1
11.
Ann Neurol ; 64(4): 446-54, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18991351

RESUMO

OBJECTIVE: We examined the epistatic effect between haplotypes of glycogen synthase kinase-3beta (GSK3B) gene and microtubule-associated protein Tau (MAPT) gene in Alzheimer's disease (AD). METHODS: A genetic association study of three AD cohorts was made. Linear regression analyses were used to examine effects of MAPT polymorphisms on gene expression and alternative splicing. beta-Catenin levels and signaling were determined using Western blot and luciferase reporter assays in cells transfected with a combination of GSK3B and MAPT complementary DNA. RESULTS: Consistent interaction between GSK3B and MAPT genes in three late-onset AD cohorts was observed, with the GSK3B haplotype (T-T) significantly increasing the risk for AD in individuals with at least one H2 haplotype (odds ratio, 1.68-2.33; p = 0.005-0.036). The GSK3B haplotype was significantly protective in the Chinese cohort (odds ratio, 0.33; p = 0.016), after adjusting for the effect of age and sex. There are significant differences in in vivo transcriptional efficiency between the two MAPT haplotypes (H1 and H2) as determined by measurement of cerebellar transcripts (p < 0.001). Overexpression of either MAPT or GSK3B resulted in decreased beta-catenin levels compared with a control vector (p < 0.001). Conversely, cotransfection of both of these molecules increased beta-catenin signaling. INTERPRETATION: Our genetic and biochemical analyses have identified a novel interaction between Tau and GSK-3beta in late-onset AD causative factors. Our data are consistent with an epistatic model of interaction where discordant levels of GSK3B and MAPT gene expression can lead to altered beta-catenin levels and pathogenicity.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Quinase 3 da Glicogênio Sintase/genética , Polimorfismo de Nucleotídeo Único , Proteínas tau/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Estudos de Casos e Controles , Linhagem Celular Transformada , Cerebelo/metabolismo , Distribuição de Qui-Quadrado , Estudos de Coortes , Feminino , Frequência do Gene , Genótipo , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Transfecção , beta Catenina/metabolismo
12.
Neurology ; 92(12): e1354-e1366, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30770429

RESUMO

OBJECTIVE: To assess the incidence, heritability, and neuropathology of primary progressive aphasia (PPA) with amyotrophic lateral sclerosis (ALS) in a large Australian cohort. METHODS: A total of 130 patients with a primary nonfluent variant of PPA (nfvPPA) or semantic variant of PPA (svPPA) were assessed for concomitant ALS and a strong family history of neurodegenerative diseases (Goldman score ≤3). Neuropathologic examination was carried out in 28% (n = 36) of these PPA and PPA-ALS cases that had come to autopsy. RESULTS: ALS was identified in 18% of patients with nfvPPA and 5% of patients with svPPA. PPA-ALS but not PPA was found to have a strong family history. At autopsy, frontotemporal lobar degeneration (FTLD)-TDP was identified in 100% of nfvPPA-ALS cases, 100% of svPPA-ALS cases, 24% of nfvPPA cases, and 78% of svPPA cases. Clinicopathologic assessments revealed a significant association between a strong family history and underlying FTLD-TDP pathology. Pathogenic mutations in known frontotemporal dementia (FTD)/ALS genes were identified in 100% of these familial PPA cases but only 50% of familial PPA-ALS cases, suggesting the involvement of novel genetic variants in this underacknowledged phenotype. CONCLUSION: The present study identified ALS in 12% of a large cohort of patients with nfvPPA and svPPA, which is comparable to the 10%-15% reported in FTD overall, indicating that a third of patients with FTD-ALS will have a predominant language profile. These findings highlight the importance of assessing for ALS in PPA, particularly since this is the only PPA phenotype in which a perfect clinicopathologic association has been reported in to date.


Assuntos
Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/patologia , Afasia Primária Progressiva/epidemiologia , Afasia Primária Progressiva/patologia , Idoso , Esclerose Lateral Amiotrófica/genética , Afasia Primária Progressiva/genética , Encéfalo/patologia , Estudos de Coortes , Feminino , Humanos , Incidência , Idioma , Masculino , Pessoa de Meia-Idade , Mutação , Estudos Retrospectivos
13.
J Neurochem ; 104(3): 573-83, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17995932

RESUMO

Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.


Assuntos
Doença de Alzheimer/complicações , Paraparesia Espástica/complicações , Fenótipo , Doença de Alzheimer/genética , Animais , Humanos , Mutação , Paraparesia Espástica/genética , Linhagem , Placa Amiloide/patologia , Presenilina-1/genética
14.
BMC Neurol ; 8: 32, 2008 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-18755042

RESUMO

BACKGROUND: Frontotemporal lobar degeneration (FTLD) represents a clinically, pathologically and genetically heterogenous neurodegenerative disorder, often complicated by neurological signs such as motor neuron-related limb weakness, spasticity and paralysis, parkinsonism and gait disturbances. Linkage to chromosome 9p had been reported for pedigrees with the neurodegenerative disorder, frontotemporal lobar degeneration (FTLD) and motor neuron disease (MND). The objective in this study is to identify the genetic locus in a multi-generational Australian family with FTLD-MND. METHODS: Clinical review and standard neuropathological analysis of brain sections from affected pedigree members. Genome-wide scan using microsatellite markers and single nucleotide polymorphism fine mapping. Examination of candidate genes by direct DNA sequencing. RESULTS: Neuropathological examination revealed cytoplasmic deposition of the TDP-43 protein in three affected individuals. Moreover, we identify a family member with clinical Alzheimer's disease, and FTLD-Ubiquitin neuropathology. Genetic linkage and haplotype analyses, defined a critical region between markers D9S169 and D9S1845 on chromosome 9p21. Screening of all candidate genes within this region did not reveal any novel genetic alterations that co-segregate with disease haplotype, suggesting that one individual carrying a meiotic recombination may represent a phenocopy. Re-analysis of linkage data using the new affection status revealed a maximal two-point LOD score of 3.24 and a multipoint LOD score of 3.41 at marker D9S1817. This provides the highest reported LOD scores from a single FTLD-MND pedigree. CONCLUSION: Our reported increase in the minimal disease region should inform other researchers that the chromosome 9 locus may be more telomeric than predicted by published recombination boundaries. Moreover, the existence of a family member with clinical Alzheimer's disease, and who shares the disease haplotype, highlights the possibility that late-onset AD patients in the other linked pedigrees may be mis-classified as sporadic dementia cases.


Assuntos
Proteínas de Ligação a DNA/genética , Demência/genética , Doença dos Neurônios Motores/genética , Neurônios Motores/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Austrália , Autopsia , Encéfalo/metabolismo , Encéfalo/patologia , Cromossomos Humanos Par 9/genética , Proteínas de Ligação a DNA/metabolismo , Demência/metabolismo , Demência/patologia , Saúde da Família , Ligação Genética , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Haplótipos , Humanos , Imuno-Histoquímica , Repetições de Microssatélites/genética , Doença dos Neurônios Motores/metabolismo , Doença dos Neurônios Motores/patologia , Neurônios Motores/patologia , Linhagem , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Ubiquitina/metabolismo , Proteínas tau/metabolismo
15.
J Alzheimers Dis ; 62(4): 1777-1787, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29614681

RESUMO

Alzheimer's disease is characterized by abnormal amyloid-ß (Aß) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aß pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-ß protein precursor (AßPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aß production and improve cognition. We firstly investigated the impact of SIGMAR1 on AßPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aß production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aß production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ∼8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aß pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AßPP processing to generate Aß, and may have a protective effect on cognition in the J20 mice.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Fluvoxamina/farmacologia , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Nootrópicos/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/genética , Animais , Animais Geneticamente Modificados , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Linhagem Celular Tumoral , Cricetulus , Modelos Animais de Doenças , Feminino , Humanos , Memória/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Polimorfismo de Nucleotídeo Único , Receptores sigma/genética , Receptores sigma/metabolismo , Receptor Sigma-1
16.
Neuroreport ; 18(12): 1267-9, 2007 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-17632280

RESUMO

Familial Alzheimer's disease due to presenilin 1 (PSEN1) mutations shows considerable phenotypic variability with differences in neuropathology and neurological symptoms. Spastic paraparesis is a common neurological phenotype associated with Alzheimer's disease arising from PSEN1 mutations. To investigate whether known genes that cause spastic paraparesis could act as Alzheimer's disease-modifier genes, we sequenced nine spastic paraparesis genes in three Alzheimer's disease families with PSEN1 exon 9 deletions. We did not observe any correlation of polymorphisms or mutations in the nine spastic paraparesis genes with the variable phenotype seen in families with Alzheimer's disease and spastic paraparesis. These results suggest a need for a continuing search for genes that cause the phenotypic variation in Alzheimer's disease and spastic paraparesis.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Predisposição Genética para Doença/genética , Mutação/genética , Paraparesia Espástica/genética , Presenilina-1/genética , Adulto , Doença de Alzheimer/fisiopatologia , Análise Mutacional de DNA , Feminino , Deleção de Genes , Marcadores Genéticos/genética , Testes Genéticos , Variação Genética/genética , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Paraparesia Espástica/fisiopatologia , Linhagem , Fenótipo
17.
Brain ; 129(Pt 11): 3124-6, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17071927

RESUMO

Mutations in presenilin-1 (PSEN1) cause autosomal dominant Alzheimer's disease and mutations in MAPT cause the familial tauopathy Frontotemporal dementia linked to chromosome 17 (FTDP-17). However, there have been reports of mutations in PSEN1 and MAPT associated with cases of FTD with ubiquitin-positive tau-negative inclusion pathology. Here, we demonstrate that the MAPT variants are almost certainly rare benign polymorphisms as all of these cases harbour mutations in Progranulin (PGRN). Mutations in PGRN were recently shown to cause ubiquitin-positive FTDP-17.


Assuntos
Demência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Mutação , Proteínas tau/genética , Sequência de Bases , Humanos , Dados de Sequência Molecular , Fenótipo , Progranulinas , Ubiquitina/metabolismo
18.
Methods Mol Biol ; 1523: 307-324, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27975259

RESUMO

Sanger sequencing is a classic technique in molecular genetics to detect single nucleotide DNA variants in genomic DNA. Here we describe the detection of MAPT mutations by polymerase chain reaction amplification of patient genomic DNA followed by bidirectional Sanger sequencing. Exon trapping is a technique whereby genomic DNA covering the exon of interest and flanking intronic sequence is cloned into the intron of an expression vector and transfected into human cell lines. RNA is extracted and splicing products are examined by reverse-transcriptase PCR and agarose gel electrophoresis. We outline the application of this technique to assess the effect of novel DNA variants on the splicing efficiency of MAPT exon 10, a common mechanism of disease for pathogenic MAPT mutations.


Assuntos
Análise Mutacional de DNA/métodos , Demência Frontotemporal/genética , Mutação/genética , Tauopatias/genética , Adulto , Éxons/genética , Feminino , Humanos , Íntrons/genética , Reação em Cadeia da Polimerase , Gravidez , Splicing de RNA/genética
19.
Alzheimers Dement (Amst) ; 9: 10-20, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28653036

RESUMO

INTRODUCTION: The diagnostic utility of in vivo amyloid ß (Aß) imaging to aid in the clinical distinction between frontotemporal dementia (FTD) and Alzheimer's disease remains unclear without data on the prevalence and severity of Aß in pathologically confirmed FTD syndromes. METHODS: Aß was assessed in 98 autopsy-confirmed FTD and 36 control cases, and the pathological accuracy of 11C-Pittsburgh compound B (PiB)-positron emission tomography imaging was assessed in a subset of FTD cases (n = 15). RESULTS: Aß was identified in a similar proportion of FTD syndromes and age-matched controls and increases with age. Alzheimer's disease pathology was identified in all cases with high PiB retention and in one case with low PiB retention. We further demonstrate a strong regional correlation between volume fraction of histological Aß with PiB standard uptake value ratio scaled to the white matter. DISCUSSION: The present study provides a pathologic reference to assist in the interpretation of in vivo assessments in FTD syndromes.

20.
PLoS One ; 11(6): e0157924, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27336847

RESUMO

Studies investigating the pathogenic role of the microtubule associated protein tau (MAPT) gene in Parkinson's disease (PD) have indicated that DNA methylation of the promoter region is aberrant in disease, leading to dysregulated MAPT expression. We examined two potential regulators of MAPT gene expression in respect to PD, a promoter-associated long non-coding RNA MAPT-AS1, and DNA methyltransferases (DNMTs), enzymes responsible for new and maintenance of DNA methylation. We assessed the relationship between expression levels of MAPT and the candidate MAPT-AS1, DNMT1, DNMT3A and DNMT3B transcripts in four brain regions with varying degrees of cell loss and pathology (putamen, anterior cingulate cortex, visual cortex and cerebellum) in N = 10 PD and N = 10 controls. We found a significant decrease in MAPT-AS1 expression in PD (p = 7.154 x 10-6). The transcript levels of both MAPT-AS1 (p = 2.569 x 10-4) and DNMT1 (p = 0.001) correlated with those of MAPT across the four brain regions, but not with each other. Overexpression of MAPT-AS1 decreased MAPT promoter activity by ∼2.2 to 4.3 fold in an in vitro luciferase assay performed in two cell lines (p ≤ 2.678 x 10-4). Knock-down expression of MAPT-AS1 led to a 1.3 to 6.3 fold increase in methylation of the endogenous MAPT promoter (p ≤ 0.011) and a 1.2 to 1.5 fold increased expression of the 4-repeat MAPT isoform transcript (p ≤ 0.013). In conclusion, MAPT-AS1 and DNMT1 have been identified as potential epigenetic regulators of MAPT expression in PD across four different brain regions. Our data also suggest that increased MAPT expression could be associated with disease state, but not with PD neuropathology severity.


Assuntos
Regulação da Expressão Gênica , Doença de Parkinson/genética , RNA Longo não Codificante/genética , Proteínas tau/genética , Biomarcadores , Encéfalo/metabolismo , Metilação de DNA , Haplótipos , Humanos , Doença de Parkinson/metabolismo , Regiões Promotoras Genéticas
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