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1.
Pestic Biochem Physiol ; 170: 104680, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32980059

RESUMO

The progression of neurodegenerative disease is very complex biological process and the molecular crosstalk of inflammatory cytokines during neurodegeneration is associated with multiple cascade signalling. Few evidences suggest that environmental toxin, Paraquat (PQ) administration activates the microglia and intensify the release of proinflamatory cytokines during progression of Parkinson''s disease (PD) but the proper aetiology remained unknown. However, the fundamental role of anti-inflammatory molecule Decapentaplegic (Dpp), homologue of the secreted mammalian Transforming growth factor-ß (TGF-ß) signalling molecule during neurodegeneration of invertebrate fly model is yet to establish. To elucidate the molecular processes during early stage of Parkinson's disease, we observed neuro-toxin plays a determining role in the increased vulnerability to a particular PQ exposure that is attended by decreased lifespan, severe locomotor deficits, and more loss of dopaminergic (DA) neuron in PQ-treated Dpp deficient fly than wild type (WT). Simultaneously, activated microglia induced the inflammatory response with the release of pro-inflammatory and anti-inflammatory cytokine in Drosophila during neurodegeneration. Moreover, neuro-toxin exposure altered the expression of innate immune genes in both WT and mutant fly compared to the respective PQ-treated flies. Interestingly, PQ exposure reduced the expression of innate immune genes in mutant fly compared to WT. It may indicate that PQ exposure had broken down the immune defence response in mutant fly than WT whereas, without PQ exposure the innate immune tolerance level was higher in fly with reduced Dpp expression than WT. Thus, we observed the conserve anti-inflammatory factor TGF-ß may exhibit a crucial defensive role during inflammation mediated neurodegeneration in invertebrate Drosophila melanogaster.


Assuntos
Proteínas de Drosophila/genética , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/genética , Animais , Modelos Animais de Doenças , Drosophila , Drosophila melanogaster/genética , Imunidade Inata/genética , Inflamação/induzido quimicamente , Inflamação/genética , Neuroglia , Paraquat/toxicidade
2.
Nat Commun ; 11(1): 4796, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32963231

RESUMO

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/ß-catenin, TGF-ß and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging.


Assuntos
Envelhecimento/genética , Encéfalo , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Doenças Neurodegenerativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estruturas Cromossômicas , Cognição , Feminino , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único
3.
PLoS One ; 15(8): e0233247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857759

RESUMO

Poly(glycine-alanine) (polyGA) is one of the polydipeptides expressed in Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 1 caused by C9ORF72 mutations and accumulates as inclusion bodies in the brain of patients. Superficially these inclusions are similar to those formed by polyglutamine (polyQ)-expanded Huntingtin exon 1 (Httex1) in Huntington's disease. Both have been reported to form an amyloid-like structure suggesting they might aggregate via similar mechanisms and therefore recruit the same repertoire of endogenous proteins. When co-expressed in the same cell, polyGA101 and Httex1(Q97) inclusions adopted immiscible phases suggesting different endogenous proteins would be enriched. Proteomic analyses identified 822 proteins in the inclusions. Only 7 were specific to polyGA and 4 specific to Httex1(Q97). Quantitation demonstrated distinct enrichment patterns for the proteins not specific to each inclusion type (up to ~8-fold normalized to total mass). The proteasome, microtubules, TriC chaperones, and translational machinery were enriched in polyGA aggregates, whereas Dnaj chaperones, nuclear envelope and RNA splicing proteins were enriched in Httex1(Q97) aggregates. Both structures revealed a collection of folding and degradation machinery including proteins in the Httex1(Q97) aggregates that are risk factors for other neurodegenerative diseases involving protein aggregation when mutated, which suggests a convergence point in the pathomechanisms of these diseases.


Assuntos
Corpos de Inclusão/metabolismo , Peptídeos/metabolismo , Proteínas/metabolismo , Animais , Proteína C9orf72/genética , Proteína C9orf72/metabolismo , Linhagem Celular , Éxons , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Corpos de Inclusão/genética , Corpos de Inclusão/patologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Microscopia Confocal , Mutação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Peptídeos/genética , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/metabolismo , Agregação Patológica de Proteínas/patologia , Proteínas/genética , Proteólise , Proteoma/genética , Proteoma/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Risco , Solubilidade
4.
Nat Commun ; 11(1): 3861, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737316

RESUMO

Integrating results from genome-wide association studies (GWASs) and gene expression studies through transcriptome-wide association study (TWAS) has the potential to shed light on the causal molecular mechanisms underlying disease etiology. Here, we present a probabilistic Mendelian randomization (MR) method, PMR-Egger, for TWAS applications. PMR-Egger relies on a MR likelihood framework that unifies many existing TWAS and MR methods, accommodates multiple correlated instruments, tests the causal effect of gene on trait in the presence of horizontal pleiotropy, and is scalable to hundreds of thousands of individuals. In simulations, PMR-Egger provides calibrated type I error control for causal effect testing in the presence of horizontal pleiotropic effects, is reasonably robust under various types of model misspecifications, is more powerful than existing TWAS/MR approaches, and can directly test for horizontal pleiotropy. We illustrate the benefits of PMR-Egger in applications to 39 diseases and complex traits obtained from three GWASs including the UK Biobank.


Assuntos
Pleiotropia Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Análise da Randomização Mendeliana/estatística & dados numéricos , Modelos Genéticos , Transcriptoma , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Simulação por Computador , Bases de Dados Factuais , Gastroenteropatias/diagnóstico , Gastroenteropatias/genética , Gastroenteropatias/patologia , Humanos , Doenças do Sistema Imunitário/diagnóstico , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Funções Verossimilhança , Doenças Metabólicas/diagnóstico , Doenças Metabólicas/genética , Doenças Metabólicas/patologia , Herança Multifatorial , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/patologia , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
5.
Am J Hum Genet ; 107(3): 539-543, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758448

RESUMO

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.


Assuntos
Doenças Neurodegenerativas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Ácido 4-Aminobenzoico/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular/efeitos dos fármacos , Feminino , Genótipo , Humanos , Mutação com Perda de Função/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Neutrófilos/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Fenótipo , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-32645824

RESUMO

Environmental lead (Pb) exposure is closely associated with pathogenesis of a range of neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), attention deficit/hyperactivity disorder (ADHD), etc. Epigenetic machinery modulates neural development and activities, while faulty epigenetic regulation contributes to the diverse forms of CNS (central nervous system) abnormalities and diseases. As a potent epigenetic modifier, lead is thought to cause neurological disorders through modulating epigenetic mechanisms. Specifically, increasing evidence linked aberrant DNA methylations, histone modifications as well as ncRNAs (non-coding RNAs) with AD cases, among which circRNA (circular RNA) stands out as a new and promising field for association studies. In 23-year-old primates with developmental lead treatment, Zawia group discovered a variety of epigenetic changes relating to AD pathogenesis. This is a direct evidence implicating epigenetic basis in lead-induced AD animals with an entire lifespan. Additionally, some epigenetic molecules associated with AD etiology were also known to respond to chronic lead exposure in comparable disease models, indicating potentially interlaced mechanisms with respect to the studied neurotoxic and pathological events. Of note, epigenetic molecules acted via globally or selectively influencing the expression of disease-related genes. Compared to AD, the association of lead exposure with other neurological disorders were primarily supported by epidemiological survey, with fewer reports connecting epigenetic regulators with lead-induced pathogenesis. Some pharmaceuticals, such as HDAC (histone deacetylase) inhibitors and DNA methylation inhibitors, were developed to deal with CNS disease by targeting epigenetic components. Still, understandings are insufficient regarding the cause-consequence relations of epigenetic factors and neurological illness. Therefore, clear evidence should be provided in future investigations to address detailed roles of novel epigenetic factors in lead-induced neurological disorders, and efforts of developing specific epigenetic therapeutics should be appraised.


Assuntos
Doença de Alzheimer , DNA/genética , Chumbo/efeitos adversos , Doenças do Sistema Nervoso/induzido quimicamente , Animais , Metilação de DNA/efeitos dos fármacos , Epigênese Genética , Inibidores de Histona Desacetilases , Doenças do Sistema Nervoso/genética , Doenças Neurodegenerativas/genética
7.
Mol Cell ; 79(3): 504-520.e9, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707033

RESUMO

Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer.


Assuntos
Redes Reguladoras de Genes , Doenças Genéticas Inatas/genética , Neoplasias/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas/genética , Biologia Computacional/métodos , Conjuntos de Dados como Assunto , Regulação da Expressão Gênica , Ontologia Genética , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/patologia , Humanos , Redes e Vias Metabólicas/genética , Anotação de Sequência Molecular , Distrofias Musculares/enzimologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Neoplasias/enzimologia , Neoplasias/patologia , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Mapeamento de Interação de Proteínas/métodos , Proteínas Quinases/química , Proteínas Quinases/classificação , Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/química , Proteínas Proto-Oncogênicas/metabolismo , Transdução de Sinais
8.
Nat Commun ; 11(1): 3391, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32636369

RESUMO

Neurodegeneration is a common hallmark of individuals with hereditary defects in DNA single-strand break repair; a process regulated by poly(ADP-ribose) metabolism. Recently, mutations in the ARH3 (ADPRHL2) hydrolase that removes ADP-ribose from proteins have been associated with neurodegenerative disease. Here, we show that ARH3-mutated patient cells accumulate mono(ADP-ribose) scars on core histones that are a molecular memory of recently repaired DNA single-strand breaks. We demonstrate that the ADP-ribose chromatin scars result in reduced endogenous levels of important chromatin modifications such as H3K9 acetylation, and that ARH3 patient cells exhibit measurable levels of deregulated transcription. Moreover, we show that the mono(ADP-ribose) scars are lost from the chromatin of ARH3-defective cells in the prolonged presence of PARP inhibition, and concomitantly that chromatin acetylation is restored to normal. Collectively, these data indicate that ARH3 can act as an eraser of ADP-ribose chromatin scars at sites of PARP activity during DNA single-strand break repair.


Assuntos
Adenosina Difosfato Ribose/química , Cromatina/química , Quebras de DNA de Cadeia Simples , Reparo do DNA , Glicosídeo Hidrolases/genética , Mutação , Linhagem Celular Tumoral , Sobrevivência Celular , Fibroblastos , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Células HEK293 , Histonas/química , Humanos , Doenças Neurodegenerativas/genética , Proteína 1 Complementadora Cruzada de Reparo de Raio-X/genética
9.
Am J Hum Genet ; 107(2): 364-373, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32707086

RESUMO

We report bi-allelic pathogenic HPDL variants as a cause of a progressive, pediatric-onset spastic movement disorder with variable clinical presentation. The single-exon gene HPDL encodes a protein of unknown function with sequence similarity to 4-hydroxyphenylpyruvate dioxygenase. Exome sequencing studies in 13 families revealed bi-allelic HPDL variants in each of the 17 individuals affected with this clinically heterogeneous autosomal-recessive neurological disorder. HPDL levels were significantly reduced in fibroblast cell lines derived from more severely affected individuals, indicating the identified HPDL variants resulted in the loss of HPDL protein. Clinical presentation ranged from severe, neonatal-onset neurodevelopmental delay with neuroimaging findings resembling mitochondrial encephalopathy to milder manifestation of adolescent-onset, isolated hereditary spastic paraplegia. All affected individuals developed spasticity predominantly of the lower limbs over the course of the disease. We demonstrated through bioinformatic and cellular studies that HPDL has a mitochondrial localization signal and consequently localizes to mitochondria suggesting a putative role in mitochondrial metabolism. Taken together, these genetic, bioinformatic, and functional studies demonstrate HPDL is a mitochondrial protein, the loss of which causes a clinically variable form of pediatric-onset spastic movement disorder.


Assuntos
Encefalopatias/genética , Proteínas Mitocondriais/genética , Doenças Neurodegenerativas/genética , Paraplegia Espástica Hereditária/genética , Adolescente , Adulto , Alelos , Sequência de Aminoácidos , Criança , Feminino , Humanos , Masculino , Mitocôndrias/genética , Linhagem , Fenótipo , Adulto Jovem
10.
Mol Cell ; 79(3): 521-534.e15, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32592681

RESUMO

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.


Assuntos
Cromatina/metabolismo , Elementos Facilitadores Genéticos , Regulação da Expressão Gênica no Desenvolvimento , Redes Reguladoras de Genes , Genoma Humano , Neurogênese/genética , Regiões Promotoras Genéticas , Adulto , Linhagem Celular , Cérebro/citologia , Cérebro/crescimento & desenvolvimento , Cérebro/metabolismo , Cromatina/ultraestrutura , Mapeamento Cromossômico , Feto , Histonas/genética , Histonas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Proteínas do Tecido Nervoso/classificação , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios/citologia , Neurônios/metabolismo , Lobo Temporal/citologia , Lobo Temporal/crescimento & desenvolvimento , Lobo Temporal/metabolismo , Fatores de Transcrição/classificação , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
11.
Neuron ; 106(6): 899-911, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32553207

RESUMO

In recent years, the nuclear pore complex (NPC) has emerged as a key player in genome regulation and cellular homeostasis. New discoveries have revealed that the NPC has multiple cellular functions besides mediating the molecular exchange between the nucleus and the cytoplasm. In this review, we discuss non-transport aspects of the NPC focusing on the NPC-genome interaction, the extreme longevity of the NPC proteins, and NPC dysfunction in age-related diseases. The examples summarized herein demonstrate that the NPC, which first evolved to enable the biochemical communication between the nucleus and the cytoplasm, now doubles as the gatekeeper of cellular identity and aging.


Assuntos
Envelhecimento/metabolismo , Esclerose Amiotrófica Lateral/metabolismo , Diferenciação Celular , Regulação da Expressão Gênica , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Poro Nuclear/metabolismo , Transporte Ativo do Núcleo Celular , Envelhecimento/genética , Senilidade Prematura/genética , Senilidade Prematura/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Esclerose Amiotrófica Lateral/genética , Animais , Proteína de Ligação a CREB/metabolismo , Senescência Celular , Genoma , Humanos , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Poro Nuclear/genética , Complexo de Proteínas Formadoras de Poros Nucleares/genética
12.
Neurology ; 95(8): e1008-e1016, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32591474

RESUMO

OBJECTIVE: To study the role of GBA variants in the risk for isolated REM sleep behavior disorder (iRBD) and conversion to overt neurodegeneration. METHODS: A total of 4,147 individuals were included: 1,061 patients with iRBD and 3,086 controls. GBA was fully sequenced using molecular inversion probes and Sanger sequencing. We analyzed the effects of GBA variants on the risk of iRBD, age at onset (AAO), and conversion rates. RESULTS: GBA variants were found in 9.5% of patients with iRBD compared to 4.1% of controls (odds ratio, 2.45; 95% confidence interval [CI], 1.87-3.22; p = 1 × 10-10). The estimated OR for mild p.N370S variant carriers was 3.69 (95% CI, 1.90-7.14; p = 3.5 × 10-5), while for severe variant carriers it was 17.55 (95% CI, 2.11-145.9; p = 0.0015). Carriers of severe GBA variants had an average AAO of 52.8 years, 7-8 years earlier than those with mild variants or noncarriers (p = 0.029). Of the GBA variant carriers with available data, 52.5% had converted, compared to 35.6% of noncarriers (p = 0.011), with a trend for faster conversion among severe GBA variant carriers. However, the results on AAO and conversion were based on small numbers and should be interpreted with caution. CONCLUSIONS: GBA variants robustly and differentially increase the risk of iRBD. The rate of conversion to neurodegeneration is also increased and may be faster among severe GBA variant carriers, although confirmation will be required in larger samples. Screening for RBD in healthy carriers of GBA variants should be studied as a potential way to identify GBA variant carriers who will develop a synucleinopathy in the future.


Assuntos
Predisposição Genética para Doença/genética , Glucosilceramidase/genética , Transtorno do Comportamento do Sono REM/genética , Idade de Início , Idoso , Progressão da Doença , Feminino , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética
13.
Nat Commun ; 11(1): 2679, 2020 05 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471994

RESUMO

The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4R269C) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4R269C triggers increased intracellular Ca2+ through a Ca2+/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca2+ and neurotoxicity in Drosophila and cultured primary mouse neurons. Importantly, TRPV4 activity impairs axonal mitochondrial transport, and TRPV4-mediated neurotoxicity is modulated by the Ca2+-binding mitochondrial GTPase Miro. Our data highlight an integral role for CaMKII in neuronal TRPV4-associated Ca2+ responses, the importance of tightly regulated Ca2+ dynamics for mitochondrial axonal transport, and the therapeutic promise of TRPV4 antagonists for patients with TRPV4-related neurodegenerative diseases.


Assuntos
Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Drosophila melanogaster/metabolismo , Doenças Neurodegenerativas/genética , Canais de Cátion TRPV/genética , Animais , Animais Geneticamente Modificados , Axônios/patologia , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Células Cultivadas , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Doenças Neurodegenerativas/patologia , Asas de Animais/crescimento & desenvolvimento
14.
Adv Exp Med Biol ; 1241: 101-124, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32383118

RESUMO

The mammalian genome mostly contains repeated sequences. Some of these repeats are in the regulatory elements of genes, and their instability, particularly the propensity to change the repeat unit number, is responsible for 36 well-known neurodegenerative human disorders. The mechanism of repeat expansion has been an unsolved question for more than 20 years. There are a few hypotheses describing models of mutation development. Every hypothesis is based on assumptions about unusual secondary structures that violate DNA metabolism processes in the cell. Some models are based on replication errors, and other models are based on mismatch repair or base excision repair errors. Additionally, it has been shown that epigenetic regulation of gene expression can influence the probability and frequency of expansion. In this review, we consider the molecular bases of repeat expansion disorders and discuss possible mechanisms of repeat expansion during cell metabolism.


Assuntos
Dano ao DNA , DNA/metabolismo , Doenças Neurodegenerativas/genética , Sequências Repetitivas de Ácido Nucleico , Animais , Reparo do DNA , Epigênese Genética , Humanos
15.
Nature ; 581(7809): 459-464, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32461653

RESUMO

Naturally occurring human genetic variants that are predicted to inactivate protein-coding genes provide an in vivo model of human gene inactivation that complements knockout studies in cells and model organisms. Here we report three key findings regarding the assessment of candidate drug targets using human loss-of-function variants. First, even essential genes, in which loss-of-function variants are not tolerated, can be highly successful as targets of inhibitory drugs. Second, in most genes, loss-of-function variants are sufficiently rare that genotype-based ascertainment of homozygous or compound heterozygous 'knockout' humans will await sample sizes that are approximately 1,000 times those presently available, unless recruitment focuses on consanguineous individuals. Third, automated variant annotation and filtering are powerful, but manual curation remains crucial for removing artefacts, and is a prerequisite for recall-by-genotype efforts. Our results provide a roadmap for human knockout studies and should guide the interpretation of loss-of-function variants in drug development.


Assuntos
Genes Essenciais/efeitos dos fármacos , Genes Essenciais/genética , Mutação com Perda de Função/genética , Terapia de Alvo Molecular , Artefatos , Automação , Consanguinidade , Éxons/genética , Mutação com Ganho de Função/genética , Frequência do Gene , Técnicas de Silenciamento de Genes , Heterozigoto , Homozigoto , Humanos , Proteína Huntingtina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doenças Neurodegenerativas/genética , Proteínas Priônicas/genética , Reprodutibilidade dos Testes , Tamanho da Amostra , Proteínas tau/genética
16.
Adv Exp Med Biol ; 1195: 237-247, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468482

RESUMO

MicroRNAs (miRNAs) are small non-coding RNA molecules of about 20-22 nucleotides. After their posttranscriptional maturation, miRNAs are loaded into the ribonucleoprotein complex RISC and modulate gene expression by binding to the 3' untranslated region of their target mRNAs through base-pairing, which in turn triggers mRNA degradation or translational inhibition. There is mounting evidence that miRNAs regulate various biological processes, including cell proliferation, differentiation, and apoptosis. Several studies have shown that miRNAs play an important role in neurogenesis and brain development.This review discusses recent progress on understanding the implication of precisely regulated miRNA expression in normal brain development and function. In addition, it reports known cases of dysregulation of miRNA expression and function implicated in the pathogenesis of neurodevelopmental disorders, craniofacial dysmorphic syndromes, neurodegenerative diseases, and psychiatric disorders. Current knowledge regarding the role of miRNAs in the brain in conjunction with the complex interplay between genetic and epigenetic factors are discussed.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , MicroRNAs/metabolismo , Regiões 3' não Traduzidas/genética , Anormalidades Craniofaciais/genética , Anormalidades Craniofaciais/metabolismo , Humanos , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , MicroRNAs/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Neurogênese/genética
18.
Nat Commun ; 11(1): 1712, 2020 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-32249849

RESUMO

The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function.


Assuntos
Neurônios Adrenérgicos/fisiologia , Envelhecimento/fisiologia , Envelhecimento Cognitivo/fisiologia , Análise de Classes Latentes , Locus Cerúleo/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Comportamento/fisiologia , Ciências Biocomportamentais , Cognição/fisiologia , Estudos de Coortes , Feminino , Humanos , Locus Cerúleo/diagnóstico por imagem , Imagem por Ressonância Magnética , Magnetoencefalografia , Masculino , Pessoa de Meia-Idade , Doenças Neurodegenerativas/genética , Adulto Jovem
19.
Rinsho Shinkeigaku ; 60(5): 317-320, 2020 May 26.
Artigo em Japonês | MEDLINE | ID: mdl-32307390

RESUMO

Beta-propeller protein-associated neurodegeneration (BPAN) is categorized in Neurodegeneration with brain iron accumulation. The clinical feature of BPAN is global developmental delay in early childhood, followed rapid progression of cognitive disfunction and parkinsonism in adulthood. This case was pointed out intellectual disability at the age of 9, followed left dominant progressive parkinsonism from the age of 31. Brain MRI showed the T1-weighted signal hyperintensity of the substantia nigra with a central band of hypointensity and the T2 star weighted image hypointensity of substantia nigra and globus pallidus presenting dominant at right side. DAT SPECT also showed specific binding ratio decreased dominant in right side. She was diagnosed BPAN based on her genetic test revealing a novel mutation (c.411dupT) in WDR45. No studies reported detailed parkinsonism like laterality in BPAN. This case indicates the left dominant parkinsonism was caused by right dominant iron deposition to substantia nigra and globus pallidus in view of MRI findings and DAT SPECT.


Assuntos
Doenças dos Gânglios da Base/etiologia , Doenças dos Gânglios da Base/genética , Proteínas de Transporte/genética , Mutação , Doenças Neurodegenerativas/genética , Adulto , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Imagem de Tensor de Difusão , Feminino , Estudos de Associação Genética , Humanos , Ferro/metabolismo , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único
20.
J Neurosci ; 40(23): 4576-4585, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32341096

RESUMO

An impediment to the development of effective therapies for neurodegenerative disease is that available animal models do not reproduce important clinical features such as adult-onset and stereotypical patterns of progression. Using in vivo magnetic resonance imaging and behavioral testing to study male and female decrepit mice, we found a stereotypical neuroanatomical pattern of progression of the lesion along the limbic system network and an associated memory impairment. Using structural variant analysis, we identified an intronic mutation in a mitochondrial-associated gene (Mrpl3) that is responsible for the decrepit phenotype. While the function of this gene is unknown, embryonic lethality in Mrpl3 knock-out mice suggests it is critical for early development. The observation that a mutation linked to energy metabolism precipitates a pattern of neurodegeneration via cell death across disparate but linked brain regions may explain how stereotyped patterns of neurodegeneration arise in humans or define a not yet identified human disease.SIGNIFICANCE STATEMENT The development of novel therapies for adult-onset neurodegenerative disease has been impeded by the limitations of available animal models in reproducing many of the clinical features. Here, we present a novel spontaneous mutation in a mitochondrial-associated gene in a mouse (termed decrepit) that results in adult-onset neurodegeneration with a stereotypical neuroanatomical pattern of progression and an associated memory impairment. The decrepit mouse model may represent a heretofore undiagnosed human disease and could serve as a new animal model to study neurodegenerative disease.


Assuntos
Variação Genética/genética , Transtornos da Memória/diagnóstico por imagem , Transtornos da Memória/genética , Proteínas Mitocondriais/genética , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Proteínas Ribossômicas/genética , Fatores Etários , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
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