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1.
EMBO J ; 42(11): e112721, 2023 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-37070548

RESUMO

Different mutations in the RNA-binding protein Pumilio1 (PUM1) cause divergent phenotypes whose severity tracks with dosage: a mutation that reduces PUM1 levels by 25% causes late-onset ataxia, whereas haploinsufficiency causes developmental delay and seizures. Yet PUM1 targets are derepressed to equal degrees in both cases, and the more severe mutation does not hinder PUM1's RNA-binding ability. We therefore considered the possibility that the severe mutation might disrupt PUM1 interactions, and identified PUM1 interactors in the murine brain. We find that mild PUM1 loss derepresses PUM1-specific targets, but the severe mutation disrupts interactions with several RNA-binding proteins and the regulation of their targets. In patient-derived cell lines, restoring PUM1 levels restores these interactors and their targets to normal levels. Our results demonstrate that dosage sensitivity does not always signify a linear relationship with protein abundance but can involve distinct mechanisms. We propose that to understand the functions of RNA-binding proteins in a physiological context will require studying their interactions as well as their targets.


Assuntos
Encéfalo , Proteínas de Ligação a RNA , Animais , Camundongos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Mutação , Encéfalo/metabolismo , Convulsões
2.
Sci Adv ; 9(7): eade4814, 2023 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-36800428

RESUMO

Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.


Assuntos
Poliadenilação , Peixe-Zebra , Animais , Humanos , Recém-Nascido , Regiões 3' não Traduzidas , Éxons , Íntrons/genética , Peixe-Zebra/genética , Embrião não Mamífero
4.
Neuron ; 110(1): 1-3, 2022 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-34990574

RESUMO

Neurodegenerative disorders can alter neural circuitry long before symptoms appear, but the path from early changes to later pathologies is obscure. In this issue of Neuron, Capizzi et al. (2021) show how early axonal growth defects in Huntington's disease create vulnerability to later degeneration.


Assuntos
Doença de Huntington , Doenças Neurodegenerativas , Humanos , Doença de Huntington/patologia , Doenças Neurodegenerativas/patologia , Neurônios/fisiologia
5.
Lancet Neurol ; 19(8): 689-698, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32702338

RESUMO

The X-linked gene encoding MECP2 is involved in two severe and complex neurodevelopmental disorders. Loss of function of the MeCP2 protein underlies Rett syndrome, whereas duplications of the MECP2 locus cause MECP2 duplication syndrome. Research on the mechanisms by which MeCP2 exerts effects on gene expression in neurons, studies of animal models bearing different disease-causing mutations, and more in-depth observations of clinical presentations have clarified some issues even as they have raised further questions. Yet there is enough evidence so far to suggest possible approaches to therapy for these two diseases that could go beyond attempting to address specific signs and symptoms (of which there are many) and instead target the pathophysiology underlying MECP2 disorders. Further work could bring antisense oligonucleotides, deep brain stimulation, and gene therapy into the clinic within the next decade or so.


Assuntos
Deficiência Intelectual Ligada ao Cromossomo X/genética , Deficiência Intelectual Ligada ao Cromossomo X/terapia , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Síndrome de Rett/genética , Síndrome de Rett/terapia , Humanos
6.
Curr Opin Neurobiol ; 63: 122-130, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32408142

RESUMO

Over the past twenty years there have been numerous advances in our understanding of Huntington's disease (HD) and other neurodegenerative proteopathies such as Alzheimer's disease and Parkinson's disease. In each case, disease-specific proteins are expressed and accumulate; what has been less clear is precisely what problems are caused by the accumulation. Recently we have begun to appreciate that increased protein levels or changes in the ratios of different isoforms affect the movement of molecules along the axon, thereby disrupting neuronal function. Huntingtin, the protein involved in HD, plays a special role in axonal transport, and very recent studies have found that its activity - and the movement of its cargoes - is altered not only in HD but in other neurological diseases. Here, we contextualize these studies and consider how modulating huntingtin activity could provide new avenues to therapy.


Assuntos
Transporte Axonal , Doença de Huntington , Humanos , Doença de Huntington/genética , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Proteínas Nucleares/metabolismo
7.
Cereb Cortex ; 30(5): 2867-2878, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31813991

RESUMO

The natural history of idiopathic Parkinson's disease (PD) varies considerably across patients. While PD is generally sporadic, there are known genetic influences: the two most common, mutations in the LRRK2 or GBA1 gene, are associated with slower and more aggressive progression, respectively. Here, we applied graph theory to metabolic brain imaging to understand the effects of genotype on the organization of previously established PD-specific networks. We found that closely matched PD patient groups with the LRRK2-G2019S mutation (PD-LRRK2) or GBA1 variants (PD-GBA) expressed the same disease networks as sporadic disease (sPD), but PD-LRRK2 and PD-GBA patients exhibited abnormal increases in network connectivity that were not present in sPD. Using a community detection strategy, we found that the location and modular distribution of these connections differed strikingly across genotypes. In PD-LRRK2, connections were gained within the network core, with the formation of distinct functional pathways linking the cerebellum and putamen. In PD-GBA, by contrast, the majority of functional connections were formed outside the core, involving corticocortical pathways at the network periphery. Strategically localized connections within the core in PD-LRRK2 may maintain PD network activity at lower levels than in PD-GBA, resulting in a less aggressive clinical course.


Assuntos
Variação Genética/fisiologia , Glucosilceramidase/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Redes e Vias Metabólicas/fisiologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/metabolismo , Estudos Transversais , Feminino , Glucosilceramidase/genética , Humanos , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/genética , Tomografia por Emissão de Pósitrons/métodos
8.
Neurology ; 87(18): 1925-1933, 2016 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-27708130

RESUMO

OBJECTIVE: To determine whether cognitive impairment in Parkinson disease (PD) and Alzheimer disease (AD) derives from the same network pathology. METHODS: We analyzed 18F-fluorodeoxyglucose PET scans from 40 patients with AD and 40 age-matched healthy controls from the Alzheimer's Disease Neuroimaging Initiative and scanned an additional 10 patients with AD and 10 healthy controls at The Feinstein Institute for Medical Research to derive an AD-related metabolic pattern (ADRP) analogous to our previously established PD cognition-related pattern (PDCP) and PD motor-related pattern (PDRP). We computed individual subject expression values for ADRP and PDCP in 89 patients with PD and correlated summary scores for cognitive functioning with network expression. We also evaluated changes in ADRP and PDCP expression in a separate group of 15 patients with PD scanned serially over a 4-year period. RESULTS: Analysis revealed a significant AD-related metabolic topography characterized by covarying metabolic reductions in the hippocampus, parahippocampal gyrus, and parietal and temporal association regions. Expression of ADRP, but not PDCP, was elevated in both AD groups and correlated with worse cognitive summary scores. Patients with PD showed slight ADRP expression, due to topographic overlap with the network underlying PD motor-related pattern degeneration, but only their PDCP expression values increased as cognitive function and executive performance declined. Longitudinal data in PD disclosed an analogous dissociation of network expression. CONCLUSIONS: Cognitive dysfunction in PD is associated with a specific brain network that is largely spatially and functionally distinct from that seen in relation to AD.


Assuntos
Doença de Alzheimer/complicações , Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Transtornos Parkinsonianos/complicações , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Análise de Variância , Estudos de Casos e Controles , Feminino , Fluordesoxiglucose F18/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Transtornos Parkinsonianos/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença
9.
Elife ; 3: e03476, 2014 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-25141375

RESUMO

The role of the hippocampus in spatial cognition is incontrovertible yet controversial. Place cells, initially thought to be location-specifiers, turn out to respond promiscuously to a wide range of stimuli. Here we test the idea, which we have recently demonstrated in a computational model, that the hippocampal place cells may ultimately be interested in a space's topological qualities (its connectivity) more than its geometry (distances and angles); such higher-order functioning would be more consistent with other known hippocampal functions. We recorded place cell activity in rats exploring morphing linear tracks that allowed us to dissociate the geometry of the track from its topology. The resulting place fields preserved the relative sequence of places visited along the track but did not vary with the metrical features of the track or the direction of the rat's movement. These results suggest a reinterpretation of previous studies and new directions for future experiments.


Assuntos
Percepção de Distância/fisiologia , Hipocampo/fisiologia , Células Receptoras Sensoriais/fisiologia , Percepção Espacial/fisiologia , Animais , Comportamento Animal , Mapeamento Encefálico , Comunicação Celular , Cognição/fisiologia , Condicionamento Clássico , Eletrodos , Hipocampo/anatomia & histologia , Hipocampo/citologia , Masculino , Movimento/fisiologia , Ratos , Ratos Long-Evans , Células Receptoras Sensoriais/citologia , Técnicas Estereotáxicas
10.
PLoS Comput Biol ; 10(6): e1003651, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24945927

RESUMO

Learning arises through the activity of large ensembles of cells, yet most of the data neuroscientists accumulate is at the level of individual neurons; we need models that can bridge this gap. We have taken spatial learning as our starting point, computationally modeling the activity of place cells using methods derived from algebraic topology, especially persistent homology. We previously showed that ensembles of hundreds of place cells could accurately encode topological information about different environments ("learn" the space) within certain values of place cell firing rate, place field size, and cell population; we called this parameter space the learning region. Here we advance the model both technically and conceptually. To make the model more physiological, we explored the effects of theta precession on spatial learning in our virtual ensembles. Theta precession, which is believed to influence learning and memory, did in fact enhance learning in our model, increasing both speed and the size of the learning region. Interestingly, theta precession also increased the number of spurious loops during simplicial complex formation. We next explored how downstream readout neurons might define co-firing by grouping together cells within different windows of time and thereby capturing different degrees of temporal overlap between spike trains. Our model's optimum coactivity window correlates well with experimental data, ranging from ∼150-200 msec. We further studied the relationship between learning time, window width, and theta precession. Our results validate our topological model for spatial learning and open new avenues for connecting data at the level of individual neurons to behavioral outcomes at the neuronal ensemble level. Finally, we analyzed the dynamics of simplicial complex formation and loop transience to propose that the simplicial complex provides a useful working description of the spatial learning process.


Assuntos
Hipocampo/fisiologia , Aprendizagem/fisiologia , Modelos Neurológicos , Animais , Comportamento Animal/fisiologia , Biologia Computacional , Conectoma , Hipocampo/citologia , Modelos Psicológicos , Ratos , Comportamento Espacial/fisiologia , Ritmo Teta/fisiologia
11.
Science ; 341(6153): 1511-4, 2013 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-24030493

RESUMO

Ensuring cooperation among formerly autonomous cells has been a central challenge in the evolution of multicellular organisms. One solution is monoclonality, but this option still leaves room for exploitative behavior, as it does not eliminate genetic and epigenetic variability. We therefore hypothesized that embryonic development must be protected by robust regulatory mechanisms that prevent aberrant clones from superseding wild-type cells. Using a genome-wide screen in murine induced pluripotent stem cells, we identified a network of genes (centered on p53, topoisomerase 1, and olfactory receptors) whose down-regulation caused the cells to replace wild-type cells in vitro and in the mouse embryo--without perturbing normal development. These genes thus appear to fulfill an unexpected role in fostering cell cooperation.


Assuntos
Desenvolvimento Embrionário/genética , Redes Reguladoras de Genes , Animais , Diferenciação Celular/genética , Transdiferenciação Celular/genética , Reprogramação Celular/genética , DNA Topoisomerases Tipo I/genética , Regulação para Baixo , Regulação da Expressão Gênica no Desenvolvimento , Estudo de Associação Genômica Ampla , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Mutação , Receptores Odorantes/genética , Proteína Supressora de Tumor p53/genética
12.
Nucleus ; 1(1): 23-9, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-21327101

RESUMO

Chromosome pairing is involved in X chromosome inactivation, a classic instance of monoallelic gene expression. Antigen receptor genes are also monoallelically expressed ("allelically excluded") by B and T lymphocytes, and we asked whether pairing contributed to the regulation of V(D)J recombination at these loci. We found that homologous immunoglobulin (Ig) alleles pair up during recombination. Homologous Ig pairing is substantially reduced in the absence of the RAG1/RAG2 recombinase, but a transgene expressing an active site RAG1 mutant (which binds but does not cleave DNA) rescues pairing in Rag1(-/-) developing B cells. RAG-mediated cleavage on one allele induces the other allele to relocate to pericentromeric heterochromatin (PCH), likely to ensure that only one allele is cut at a time. This relocation to PCH requires the DNA damage sensor ATM (ataxia telengiectasia mutated). In the absence of ATM, repositioning at PCH is diminished and the incidence of cleavage on both alleles is significantly increased. ATM appears to be activated by the introduction of a double-strand break on one allele to act in trans on the uncleaved allele, repositioning or maintaining it at PCH, to prevent bi-allelic recombination and chromosomal translocations.


Assuntos
Alelos , Recombinação V(D)J/genética , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular , Cromossomos/metabolismo , Reparo do DNA , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Instabilidade Genômica , Histonas/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Imunoglobulinas/genética , Camundongos , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Supressoras de Tumor/antagonistas & inibidores , Proteínas Supressoras de Tumor/metabolismo
13.
Adv Exp Med Biol ; 650: 32-45, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19731799

RESUMO

Chromosomal translocations are found in many types of tumors, where they may be either a cause or a result of malignant transformation. In lymphoid neoplasms, however, it is dear that pathogenesis is initiated by any of a number of recurrent DNA rearrangements. These particular translocations typically place an oncogene under the regulatory control of an Ig or TCR gene promoter, dysregulating cell growth, differentiation, or apoptosis. Given that physiological DNA rearrangements (V(D)J and class switch recombination) are integral to lymphocyte development, it is critical to understand how genomic stability is maintained during these processes. Recent advances in our understanding of DNA damage signaling and repair have provided clues to the kinds of mechanisms that lead to V(D)J-mediated translocations. In turn, investigations into the regulation of V(D)J joining have illuminated a formerly obscure pathway of DNA repair known as alternative NHEJ, which is error-prone and frequently involved in translocations. In this chapter we consider recent advances in our understanding of the functions of the RAG proteins, RAG interactions with DNA repair pathways, damage signaling and chromosome biology, all of which shed light on how mistakes at different stages of V(D)J recombination might lead to leukemias and lymphomas.


Assuntos
Rearranjo Gênico , Proteínas de Homeodomínio/metabolismo , Recombinação Genética , Translocação Genética , Animais , Dano ao DNA , Reparo do DNA , Proteínas de Homeodomínio/genética , Humanos , Sinais Direcionadores de Proteínas , VDJ Recombinases/metabolismo
15.
Nature ; 449(7161): 483-6, 2007 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-17898768

RESUMO

Mammalian cells repair DNA double-strand breaks (DSBs) through either homologous recombination or non-homologous end joining (NHEJ). V(D)J recombination, a cut-and-paste mechanism for generating diversity in antigen receptors, relies on NHEJ for repairing DSBs introduced by the Rag1-Rag2 protein complex. Animals lacking any of the seven known NHEJ factors are therefore immunodeficient. Nevertheless, DSB repair is not eliminated entirely in these animals: evidence of a third mechanism, 'alternative NHEJ', appears in the form of extremely rare V(D)J junctions and a higher rate of chromosomal translocations. The paucity of these V(D)J events has suggested that alternative NHEJ contributes little to a cell's overall repair capacity, being operative only (and inefficiently) when classical NHEJ fails. Here we find that removing certain portions of murine Rag proteins reveals robust alternative NHEJ activity in NHEJ-deficient cells and some alternative joining activity even in wild-type cells. We propose a two-tier model in which the Rag proteins collaborate with NHEJ factors to preserve genomic integrity during V(D)J recombination.


Assuntos
Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Recombinação Genética/genética , Animais , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/deficiência , Proteínas de Homeodomínio/química , Camundongos , Modelos Genéticos , Mutação/genética
16.
Nat Struct Mol Biol ; 13(11): 1010-5, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17028591

RESUMO

The Rag proteins carry out V(D)J recombination through a process mechanistically similar to cut-and-paste transposition. Specifically, Rag complexes form DNA hairpins through direct transesterification, using a catalytic Asp-Asp-Glu (DDE) triad in Rag1. How is sufficient DNA distortion introduced to allow hairpin formation? We hypothesized that, like certain transposases, the Rag proteins might use aromatic amino acid residues to stabilize a flipped-out base. Through in vivo and in vitro experiments and structural predictions, we identified residues in Rag1 crucial for hairpin formation. One of these, a conserved tryptophan (Trp893), probably participates in base-stacking interactions near the cleavage site, as do Trp298, Trp265 and Trp319 in the Tn5, Tn10 and Hermes transposases, respectively. Other residues surrounding the catalytic glutamate (YKEFRK) may share functional similarities with the YREK motif in IS4 family transposases.


Assuntos
Aminoácidos Aromáticos/metabolismo , DNA/química , DNA/metabolismo , Proteínas de Homeodomínio/química , Proteínas de Homeodomínio/metabolismo , Sequência de Aminoácidos , Aminoácidos Aromáticos/análise , Aminoácidos Aromáticos/genética , Animais , Células CHO , Domínio Catalítico , Sequência Conservada , Cricetinae , Proteínas de Homeodomínio/genética , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Conformação de Ácido Nucleico , Alinhamento de Sequência , Relação Estrutura-Atividade , Transposases/química , Transposases/metabolismo , VDJ Recombinases/química , VDJ Recombinases/genética , VDJ Recombinases/metabolismo
18.
Mol Cell ; 16(4): 505-8, 2004 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-15546611

RESUMO

The mechanisms underlying somatic hypermutation (SHM) and class switch recombination (CSR) have been the subject of much debate. Recent studies from the Neuberger and Honjo labs have lent insight into these distinct processes, and we discuss a new, comprehensive model for how AID, uracil DNA glycosylase (UNG) and the mismatch repair system function in both SHM and CSR.


Assuntos
Linfócitos B/metabolismo , Pareamento Incorreto de Bases , Switching de Imunoglobulina/genética , Hipermutação Somática de Imunoglobulina/genética , Animais , Linfócitos B/enzimologia , Linfócitos B/imunologia , Pareamento Incorreto de Bases/imunologia , Citidina Desaminase/metabolismo , DNA Glicosilases/metabolismo , Reparo do DNA , Humanos , Modelos Imunológicos , Edição de RNA , Uracila-DNA Glicosidase
19.
Immunol Rev ; 200: 249-60, 2004 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15242410

RESUMO

Since the discovery that the recombination-activating gene (RAG) proteins were capable of transposition in vitro, investigators have been trying to uncover instances of transposition in vivo and understand how this transposase has been harnessed to do useful work while being inhibited from causing deleterious chromosome rearrangements. How to preserve the capacity of the recombinase to promote a certain class of rearrangements while curtailing its ability to catalyze others is an interesting problem. In this review, we examine the progress that has been made toward understanding the regulatory mechanisms that prohibit transposition in order to formulate a model that takes into account the diverse observations that have been made over the last 15 years. First, we touch on the striking mechanistic similarities between transposition and V(D)J recombination and review evidence suggesting that the RAG proteins may be members of the retroviral integrase superfamily. We then dispense with an old theory that certain standard products of V(D)J recombination called signal joints protect against deleterious transposition events. Finally, we discuss the evidence that target capture could serve a regulatory role and close with an analysis of hairpins as preferred targets for RAG-mediated transposition. These novel strategies for harnessing the RAG transposase not only shed light on V(D)J recombination but also may provide insight into the regulation of other transposases.


Assuntos
Proteínas de Ligação a DNA/fisiologia , Rearranjo Gênico do Linfócito B , Rearranjo Gênico do Linfócito T , Proteínas de Homeodomínio/fisiologia , Transposases/metabolismo , Esterificação , Humanos , Proteínas Nucleares , Recombinação Genética , Transposases/química , Transposases/genética , VDJ Recombinases/imunologia , VDJ Recombinases/metabolismo
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