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1.
Hum Mutat ; 41(1): 169-181, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31464095

RESUMO

Rare coding variants in the triggering receptor expressed on myeloid cells-2 (TREM2) gene have been associated with Alzheimer disease (AD) and homozygous TREM2 loss-of-function variants have been reported in families with monogenic frontotemporal-like dementia with/without bone abnormalities. In a whole-exome sequencing study of a family with probable AD-type dementia without pathogenic variants in known autosomal dominant dementia disease genes and negative for the apolipoprotein E (APOE) ε4 allele, we identified an extremely rare TREM2 coding variant, that is, a glycine-to-tryptophan substitution at amino acid position 145 (NM_018965.3:c.433G>T/p.[Gly145Trp]). This alteration is found in only 1 of 251,150 control alleles in gnomAD. It was present in both severely affected as well as in another putatively affected and one 61 years old as yet unaffected family member suggesting incomplete penetrance and/or a variable age of onset. Gly145 maps to an intrinsically disordered region (IDR) of TREM2 between the immunoglobulin-like and transmembrane domain. Subsequent cellular studies showed that the variant led to IDR shortening and structural changes of the mutant protein resulting in an impairment of cellular responses upon receptor activation. Our results, suggest that a p.(Gly145Trp)-induced structural disturbance and functional impairment of TREM2 may contribute to the pathogenesis of an AD-like form of dementia.


Assuntos
Demência/diagnóstico , Demência/genética , Predisposição Genética para Doença , Variação Genética , Heterozigoto , Proteínas Intrinsicamente Desordenadas/genética , Glicoproteínas de Membrana/genética , Receptores Imunológicos/genética , Idoso , Alelos , Animais , Linhagem Celular , Feminino , Estudos de Associação Genética , Humanos , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Fases de Leitura Aberta/genética , Linhagem , Fenótipo , Transporte Proteico , Receptores Imunológicos/metabolismo , Transdução de Sinais , Sequenciamento do Exoma
2.
Acta Neuropathol ; 139(6): 1025-1044, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32166339

RESUMO

A rare coding variant (rs72824905, p.P522R) conferring protection against Alzheimer's disease (AD) was identified in the gene encoding the enzyme phospholipase-C-γ2 (PLCG2) that is highly expressed in microglia. To explore the protective nature of this variant, we employed latent process linear mixed models to examine the association of p.P522R with longitudinal cognitive decline in 3595 MCI patients, and in 10,097 individuals from population-based studies. Furthermore, association with CSF levels of pTau181, total tau, and Aß1-42 was assessed in 1261 MCI patients. We found that MCI patients who carried the p.P522R variant showed a slower rate of cognitive decline compared to non-carriers and that this effect was mediated by lower pTau181 levels in CSF. The effect size of the association of p.P522R with the cognitive decline and pTau181 was similar to that of APOE-ε4, the strongest genetic risk factor for AD. Interestingly, the protective effect of p.P522R was more pronounced in MCI patients with low Aß1-42 levels suggesting a role of PLCG2 in the response to amyloid pathology. In line with this hypothesis, we observed no protective effect of the PLCG2 variant on the cognitive decline in population-based studies probably due to the lower prevalence of amyloid positivity in these samples compared to MCI patients. Concerning the potential biological underpinnings, we identified a network of co-expressed proteins connecting PLCG2 to APOE and TREM2 using unsupervised co-regulatory network analysis. The network was highly enriched for the complement cascade and genes differentially expressed in disease-associated microglia. Our data show that p.P522R in PLCG2 reduces AD disease progression by mitigating tau pathology in the presence of amyloid pathology and, as a consequence, maintains cognitive function. Targeting the enzyme PLCG2 might provide a new therapeutic approach for treating AD.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Fosfolipase C gama/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Biomarcadores/análise , Cognição/fisiologia , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismo
3.
Brain ; 140(6): 1561-1578, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28459997

RESUMO

Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10-4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.


Assuntos
Deficiência Intelectual/genética , Espasticidade Muscular/genética , Atrofia Óptica/genética , RNA Polimerase III/genética , Paraplegia Espástica Hereditária/genética , Ataxias Espinocerebelares/genética , Idoso , Técnicas de Cultura de Células , Éxons/genética , Feminino , Estudos de Associação Genética , Humanos , Células-Tronco Pluripotentes Induzidas , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/fisiopatologia , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/fisiopatologia , Mutação , Atrofia Óptica/diagnóstico por imagem , Atrofia Óptica/fisiopatologia , Linhagem , Fenótipo , Paraplegia Espástica Hereditária/diagnóstico por imagem , Paraplegia Espástica Hereditária/fisiopatologia , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/fisiopatologia
4.
J Biol Chem ; 291(20): 10528-40, 2016 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-26957541

RESUMO

The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, α-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-ß peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Trealose/metabolismo , Trealose/farmacologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Autofagia/efeitos dos fármacos , Linhagem Celular , Células HEK293 , Células Hep G2 , Humanos , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Camundongos , Fragmentos de Peptídeos/metabolismo , Transporte Proteico/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Serina-Treonina Quinases TOR/metabolismo
5.
J Neuroinflammation ; 13: 17, 2016 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-26792193

RESUMO

BACKGROUND: Triggering receptor expressed on myeloid cells-2 (TREM2) exerts important functions in the regulation of monocytes, like dendritic cells, osteoclasts, tissue macrophages, and microglia. Mutations in TREM2 are associated with several diseases, including Nasu-Hakola disease, frontotemporal dementia, and Alzheimer's disease (AD). TREM2 undergoes sequential proteolytic processing by ectodomain shedding and intramembrane proteolysis. FINDINGS: We show that inhibition of γ-secretase-dependent cleavage of the TREM2 C-terminal fragment in cellular membranes interferes with TREM2-dependent signaling and cellular function. Inhibition of γ-secretase decreases membrane-proximal signaling and intracellular Ca(2+) response. Decreased signaling alters morphological changes and phagocytic activity of cells upon selective stimulation of TREM2. CONCLUSIONS: The data demonstrate the importance of γ-secretase-dependent intramembrane processing in TREM2-mediated signaling and, thus, a functional relation of two AD-associated proteins.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Glicoproteínas de Membrana/metabolismo , Células Mieloides/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais/fisiologia , Animais , Células COS , Sinalização do Cálcio/fisiologia , Linhagem Celular Transformada , Chlorocebus aethiops , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Glicoproteínas de Membrana/genética , Camundongos , Microglia/metabolismo , Modelos Biológicos , Fagocitose/fisiologia , Receptores Imunológicos/genética , Fatores de Tempo , Transfecção
6.
J Biol Chem ; 289(24): 16761-72, 2014 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-24808180

RESUMO

Progressive accumulation of the amyloid ß protein in extracellular plaques is a neuropathological hallmark of Alzheimer disease. Amyloid ß is generated during sequential cleavage of the amyloid precursor protein (APP) by ß- and γ-secretases. In addition to the proteolytic processing by secretases, APP is also metabolized by lysosomal proteases. Here, we show that accumulation of intracellular sphingosine-1-phosphate (S1P) impairs the metabolism of APP. Cells lacking functional S1P-lyase, which degrades intracellular S1P, strongly accumulate full-length APP and its potentially amyloidogenic C-terminal fragments (CTFs) as compared with cells expressing the functional enzyme. By cell biological and biochemical methods, we demonstrate that intracellular inhibition of S1P-lyase impairs the degradation of APP and CTFs in lysosomal compartments and also decreases the activity of γ-secretase. Interestingly, the strong accumulation of APP and CTFs in S1P-lyase-deficient cells was reversed by selective mobilization of Ca(2+) from the endoplasmic reticulum or lysosomes. Intracellular accumulation of S1P also impairs maturation of cathepsin D and degradation of Lamp-2, indicating a general impairment of lysosomal activity. Together, these data demonstrate that S1P-lyase plays a critical role in the regulation of lysosomal activity and the metabolism of APP.


Assuntos
Aldeído Liases/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/metabolismo , Lisossomos/metabolismo , Aldeído Liases/genética , Aldeído Liases/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Cálcio/metabolismo , Catepsina D/metabolismo , Células HEK293 , Humanos , Lisofosfolipídeos/metabolismo , Proteína 2 de Membrana Associada ao Lisossomo/metabolismo , Camundongos , Proteólise , Esfingosina/análogos & derivados , Esfingosina/metabolismo
7.
Cell Physiol Biochem ; 34(1): 148-57, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24977488

RESUMO

Sphingosine-1-phosphate (S1P), an evolutionary conserved bioactive lipid, is essential for brain development, but might also exert detrimental effects in terminally differentiated post-mitotic neurons. Its concentration in the brain is tightly regulated by specific kinases and phosphatases, and mainly by the S1P degrading enzyme, S1P-lyase (S1PL). The role of S1P in neurons was initially studied in primary cultures by using structural analogues. During the last 3 years generation of a S1PL deficient mouse model substantially promoted our knowledge on the functional role of S1P metabolism in the brain, and its potential relation to neurodegenerative diseases. However, our understanding of the molecular mechanisms that underlie the physiological and pathophysiological actions of S1P in neurons remains rather scarce.


Assuntos
Encéfalo/metabolismo , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Aldeído Liases/deficiência , Aldeído Liases/genética , Aldeído Liases/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Lisofosfolipídeos/química , Esfingosina/química , Esfingosina/metabolismo , Proteínas tau/metabolismo
8.
World J Biol Psychiatry ; 19(4): 244-328, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29076399

RESUMO

In the 12 years since the publication of the first Consensus Paper of the WFSBP on biomarkers of neurodegenerative dementias, enormous advancement has taken place in the field, and the Task Force takes now the opportunity to extend and update the original paper. New concepts of Alzheimer's disease (AD) and the conceptual interactions between AD and dementia due to AD were developed, resulting in two sets for diagnostic/research criteria. Procedures for pre-analytical sample handling, biobanking, analyses and post-analytical interpretation of the results were intensively studied and optimised. A global quality control project was introduced to evaluate and monitor the inter-centre variability in measurements with the goal of harmonisation of results. Contexts of use and how to approach candidate biomarkers in biological specimens other than cerebrospinal fluid (CSF), e.g. blood, were precisely defined. Important development was achieved in neuroimaging techniques, including studies comparing amyloid-ß positron emission tomography results to fluid-based modalities. Similarly, development in research laboratory technologies, such as ultra-sensitive methods, raises our hopes to further improve analytical and diagnostic accuracy of classic and novel candidate biomarkers. Synergistically, advancement in clinical trials of anti-dementia therapies energises and motivates the efforts to find and optimise the most reliable early diagnostic modalities. Finally, the first studies were published addressing the potential of cost-effectiveness of the biomarkers-based diagnosis of neurodegenerative disorders.


Assuntos
Psiquiatria Biológica/normas , Biomarcadores , Consenso , Demência/diagnóstico , Doenças Neurodegenerativas/diagnóstico , Sociedades Médicas/normas , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Demência/sangue , Demência/líquido cefalorraquidiano , Humanos , Doenças Neurodegenerativas/sangue , Doenças Neurodegenerativas/líquido cefalorraquidiano
9.
PLoS One ; 12(10): e0185777, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28985224

RESUMO

The accumulation of amyloid beta (Aß) peptide (Amyloid cascade hypothesis), an APP protein cleavage product, is a leading hypothesis in the etiology of Alzheimer's disease (AD). In order to identify additional AD risk genes, we performed targeted sequencing and rare variant burden association study for nine candidate genes involved in the amyloid metabolism in 1886 AD cases and 1700 controls. We identified a significant variant burden association for the gene encoding caspase-8, CASP8 (p = 8.6x10-5). For two CASP8 variants, p.K148R and p.I298V, the association remained significant in a combined sample of 10,820 cases and 8,881 controls. For both variants we performed bioinformatics structural, expression and enzymatic activity studies and obtained evidence for loss of function effects. In addition to their role in amyloid processing, caspase-8 and its downstream effector caspase-3 are involved in synaptic plasticity, learning, memory and control of microglia pro-inflammatory activation and associated neurotoxicity, indicating additional mechanisms that might contribute to AD. As caspase inhibition has been proposed as a mechanism for AD treatment, our finding that AD-associated CASP8 variants reduce caspase function calls for caution and is an impetus for further studies on the role of caspases in AD and other neurodegenerative diseases.


Assuntos
Alelos , Doença de Alzheimer/genética , Caspase 8/genética , Variação Genética , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Caspase 8/metabolismo , Linhagem Celular Tumoral , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Neurônios/metabolismo
10.
Epigenomics ; 8(5): 593-8, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-27092400

RESUMO

Alterations in DNA methylation have been associated with cognitive decline and Alzheimer's disease. A recent study of mild cognitive impairment (MCI) reported a significant association between annual decline in cognitive function and the rs11887120 SNP located in DNMT3A, a gene implicated in DNA methylation. Here, we aimed to replicate this finding in two independent MCI cohorts (n = 1024); however, no significant association was observed in either cohort or the pooled dataset. In stratified analyses for conversion to Alzheimer's disease status, no association between rs11887120 and cognitive decline was observed in either converters or nonconverters. In conclusion, our analyses provide no support for the hypothesis that genetic variants in DNMT3A are implicated in cognitive performance decline in individuals with MCI.


Assuntos
Doença de Alzheimer/genética , Disfunção Cognitiva/genética , DNA (Citosina-5-)-Metiltransferases/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/psicologia , Estudos de Casos e Controles , Cognição , Disfunção Cognitiva/psicologia , DNA Metiltransferase 3A , Progressão da Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único
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