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1.
Annu Rev Neurosci ; 2024 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-38663088

RESUMO

Over 40% of the human genome is composed of retrotransposons, DNA species that hold the potential to replicate via an RNA intermediate and are evolutionarily related to retroviruses. Retrotransposons are most studied for their ability to jump within a genome, which can cause DNA damage and novel insertional mutations. Retrotransposon-encoded products, including viral-like proteins, double-stranded RNAs, and extrachromosomal cytoplasmic DNAs, can also be potent activators of the innate immune system. A growing body of evidence suggests that retrotransposons are activated in age-related neurodegenerative disorders and that such activation causally contributes to neurotoxicity. Here we provide an overview of retrotransposon biology and outline evidence of retrotransposon activation in age-related neurodegenerative disorders, with an emphasis on those involving TAR-DNA binding protein-43 (TDP-43) and tau. Studies to date provide the basis for ongoing clinical trials and hold promise for innovative strategies to ameliorate the adverse effects of retrotransposon dysregulation in neurodegenerative disorders.

2.
PLoS Genet ; 19(9): e1010973, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37747929

RESUMO

Accumulation of cytoplasmic inclusions of TAR-DNA binding protein 43 (TDP-43) is seen in both neurons and glia in a range of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Alzheimer's disease (AD). Disease progression involves non-cell autonomous interactions among multiple cell types, including neurons, microglia and astrocytes. We investigated the effects in Drosophila of inducible, glial cell type-specific TDP-43 overexpression, a model that causes TDP-43 protein pathology including loss of nuclear TDP-43 and accumulation of cytoplasmic inclusions. We report that TDP-43 pathology in Drosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown of SF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan and SF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.


Assuntos
Esclerose Lateral Amiotrófica , Proteínas de Drosophila , Demência Frontotemporal , Animais , Esclerose Lateral Amiotrófica/genética , Astrócitos/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Neurônios/metabolismo , Fatores de Processamento de RNA/metabolismo
3.
Nat Commun ; 14(1): 966, 2023 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-36810738

RESUMO

Inter-cellular movement of "prion-like" proteins is thought to explain propagation of neurodegeneration between cells. For example, propagation of abnormally phosphorylated cytoplasmic inclusions of TAR-DNA-Binding protein (TDP-43) is proposed to underlie progression of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). But unlike transmissible prion diseases, ALS and FTD are not infectious and injection of aggregated TDP-43 is not sufficient to cause disease. This suggests a missing component of a positive feedback necessary to sustain disease progression. We demonstrate that endogenous retrovirus (ERV) expression and TDP-43 proteinopathy are mutually reinforcing. Expression of either Drosophila mdg4-ERV (gypsy) or the human ERV, HERV-K (HML-2) are each sufficient to stimulate cytoplasmic aggregation of human TDP-43. Viral ERV transmission also triggers TDP-43 pathology in recipient cells that express physiological levels of TDP-43, whether they are in contact or at a distance. This mechanism potentially underlies the TDP-43 proteinopathy-caused neurodegenerative propagation through neuronal tissue.


Assuntos
Esclerose Lateral Amiotrófica , Retrovirus Endógenos , Demência Frontotemporal , Proteinopatias TDP-43 , Animais , Humanos , Retrovirus Endógenos/metabolismo , Esclerose Lateral Amiotrófica/genética , Demência Frontotemporal/genética , Drosophila/metabolismo , Retroalimentação , Proteinopatias TDP-43/metabolismo , Proteínas de Ligação a DNA/metabolismo
4.
PLoS Genet ; 17(11): e1009882, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34723963

RESUMO

Cytoplasmic aggregation of Tar-DNA/RNA binding protein 43 (TDP-43) occurs in 97 percent of amyotrophic lateral sclerosis (ALS), ~40% of frontotemporal dementia (FTD) and in many cases of Alzheimer's disease (AD). Cytoplasmic TDP-43 inclusions are seen in both sporadic and familial forms of these disorders, including those cases that are caused by repeat expansion mutations in the C9orf72 gene. To identify downstream mediators of TDP-43 toxicity, we expressed human TDP-43 in a subset of Drosophila motor neurons. Such expression causes age-dependent deficits in negative geotaxis behavior. Using this behavioral readout of locomotion, we conducted an shRNA suppressor screen and identified 32 transcripts whose knockdown was sufficient to ameliorate the neurological phenotype. The majority of these suppressors also substantially suppressed the negative effects on lifespan seen with glial TDP-43 expression. In addition to identification of a number of genes whose roles in neurodegeneration were not previously known, our screen also yielded genes involved in chromatin regulation and nuclear/import export- pathways that were previously identified in the context of cell based or neurodevelopmental suppressor screens. A notable example is SF2, a conserved orthologue of mammalian SRSF1, an RNA binding protein with roles in splicing and nuclear export. Our identification SF2/SRSF1 as a potent suppressor of both neuronal and glial TDP-43 toxicity also provides a convergence with C9orf72 expansion repeat mediated neurodegeneration, where this gene also acts as a downstream mediator.


Assuntos
Envelhecimento/metabolismo , Proteínas de Ligação a DNA/metabolismo , Neurônios Motores/metabolismo , Neuroglia/metabolismo , Fatores de Processamento de Serina-Arginina/metabolismo , Animais , Animais Geneticamente Modificados , Sistemas CRISPR-Cas , Humanos
5.
PLoS Genet ; 17(4): e1009535, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33886543

RESUMO

It has become increasingly clear that retrotransposons (RTEs) are more widely expressed in somatic tissues than previously appreciated. RTE expression has been implicated in a myriad of biological processes ranging from normal development and aging, to age related diseases such as cancer and neurodegeneration. Long Terminal Repeat (LTR)-RTEs are evolutionary ancestors to, and share many features with, exogenous retroviruses. In fact, many organisms contain endogenous retroviruses (ERVs) derived from exogenous retroviruses that integrated into the germ line. These ERVs are inherited in Mendelian fashion like RTEs, and some retain the ability to transmit between cells like viruses, while others develop the ability to act as RTEs. The process of evolutionary transition between LTR-RTE and retroviruses is thought to involve multiple steps by which the element loses or gains the ability to transmit copies between cells versus the ability to replicate intracellularly. But, typically, these two modes of transmission are incompatible because they require assembly in different sub-cellular compartments. Like murine IAP/IAP-E elements, the gypsy family of retroelements in arthropods appear to sit along this evolutionary transition. Indeed, there is some evidence that gypsy may exhibit retroviral properties. Given that gypsy elements have been found to actively mobilize in neurons and glial cells during normal aging and in models of neurodegeneration, this raises the question of whether gypsy replication in somatic cells occurs via intracellular retrotransposition, intercellular viral spread, or some combination of the two. These modes of replication in somatic tissues would have quite different biological implications. Here, we demonstrate that Drosophila gypsy is capable of both cell-associated and cell-free viral transmission between cultured S2 cells of somatic origin. Further, we demonstrate that the ability of gypsy to move between cells is dependent upon a functional copy of its viral envelope protein. This argues that the gypsy element has transitioned from an RTE into a functional endogenous retrovirus with the acquisition of its envelope gene. On the other hand, we also find that intracellular retrotransposition of the same genomic copy of gypsy can occur in the absence of the Env protein. Thus, gypsy exhibits both intracellular retrotransposition and intercellular viral transmission as modes of replicating its genome.


Assuntos
Drosophila melanogaster/genética , Retrovirus Endógenos/genética , Evolução Molecular , Retroelementos/genética , Animais , Humanos , Camundongos , Neoplasias/genética , Neoplasias/virologia , Degeneração Neural/genética , Degeneração Neural/virologia , Neurônios/metabolismo , Neurônios/patologia , Neurônios/virologia , Sequências Repetidas Terminais/genética
6.
Curr Biol ; 31(2): R55-R57, 2021 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-33497627

RESUMO

Interview with Josh Dubnau, who studies the role of mobile retrotransposable elements on both normal brain aging and age-related neurodegenerative diseases at Stony Brook University.


Assuntos
Biologia do Desenvolvimento , Animais , Pesquisa Biomédica , Drosophila/crescimento & desenvolvimento , Docentes , Humanos , Pesquisadores , Faculdades de Medicina/organização & administração
7.
Cell Rep ; 29(5): 1164-1177.e5, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31665631

RESUMO

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the progressive loss of motor neurons. While several pathogenic mutations have been identified, the vast majority of ALS cases have no family history of disease. Thus, for most ALS cases, the disease may be a product of multiple pathways contributing to varying degrees in each patient. Using machine learning algorithms, we stratify the transcriptomes of 148 ALS postmortem cortex samples into three distinct molecular subtypes. The largest cluster, identified in 61% of patient samples, displays hallmarks of oxidative and proteotoxic stress. Another 19% of the samples shows predominant signatures of glial activation. Finally, a third group (20%) exhibits high levels of retrotransposon expression and signatures of TARDBP/TDP-43 dysfunction. We further demonstrate that TDP-43 (1) directly binds a subset of retrotransposon transcripts and contributes to their silencing in vitro, and (2) pathological TDP-43 aggregation correlates with retrotransposon de-silencing in vivo.


Assuntos
Esclerose Lateral Amiotrófica/classificação , Esclerose Lateral Amiotrófica/patologia , Córtex Cerebral/patologia , Neuroglia/patologia , Estresse Oxidativo , Mudanças Depois da Morte , Retroelementos/genética , Esclerose Lateral Amiotrófica/genética , Biomarcadores/metabolismo , Linhagem Celular , Estudos de Coortes , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Inativação Gênica , Humanos , Estresse Oxidativo/genética , Ligação Proteica/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/genética
8.
Curr Biol ; 29(19): 3135-3152.e4, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31495585

RESUMO

A hallmark of neurodegenerative disease is focal onset of pathological protein aggregation, followed by progressive spread of pathology to connected brain regions. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), pathology is often associated with aggregation of TAR DNA-binding protein 43 (TDP-43). Although aggregated TDP-43 protein moves between cells, it is not clear whether and how this movement propagates the degeneration. Here, we have established a Drosophila model of human TDP-43 in which we initiated toxic expression of human TDP-43 focally within small groups of glial cells. We found that this focal onset kills adjacent neurons. Surprisingly, we show that this spreading death is caused by an endogenous retrovirus within the glia, which leads to DNA damage and death in adjacent neurons. These findings suggest a possible mechanism by which human retroviruses such as HERV-K might contribute to TDP-43-mediated propagation of neurodegeneration.


Assuntos
Proteínas de Ligação a DNA/farmacologia , Proteínas de Drosophila/farmacologia , Drosophila melanogaster , Retrovirus Endógenos/fisiologia , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/fisiopatologia , Neuroglia/patologia , Animais , Modelos Animais de Doenças , Drosophila melanogaster/virologia , Doenças Neurodegenerativas/virologia , Neuroglia/virologia
9.
PLoS Biol ; 17(5): e3000278, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31095565

RESUMO

Evidence is rapidly mounting that transposable element (TE) expression and replication may impact biology more widely than previously thought. This includes potential effects on normal physiology of somatic tissues and dysfunctional impacts in diseases associated with aging, such as cancer and neurodegeneration. Investigation of the biological impact of mobile elements in somatic cells will be greatly facilitated by the use of donor elements that are engineered to report de novo events in vivo. In multicellular organisms, reporter constructs demonstrating engineered long interspersed nuclear element (LINE-1; L1) mobilization have been in use for quite some time, and strategies similar to L1 retrotransposition reporter assays have been developed to report replication of Ty1 elements in yeast and mouse intracisternal A particle (IAP) long terminal repeat (LTR) retrotransposons in cultivated cells. We describe a novel approach termed cellular labeling of endogenous retrovirus replication (CLEVR), which reports replication of the gypsy element within specific cells in vivo in Drosophila. The gypsy-CLEVR reporter reveals gypsy replication both in cell culture and in individual neurons and glial cells of the aging adult fly. We also demonstrate that the gypsy-CLEVR replication rate is increased when the short interfering RNA (siRNA) silencing system is genetically disrupted. This CLEVR strategy makes use of universally conserved features of retroviruses and should be widely applicable to other LTR retrotransposons, endogenous retroviruses (ERVs), and exogenous retroviruses.


Assuntos
Envelhecimento/genética , Técnicas de Cultura de Células/métodos , Drosophila melanogaster/genética , Retrovirus Endógenos/fisiologia , Neuroglia/metabolismo , Neurônios/metabolismo , Retroelementos/genética , Replicação Viral/fisiologia , Animais , Senescência Celular/genética , Drosophila melanogaster/fisiologia , Retrovirus Endógenos/genética , Genes Reporter , Engenharia Genética , Mutação/genética , Coloração e Rotulagem
10.
G3 (Bethesda) ; 9(1): 81-94, 2019 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-30397017

RESUMO

The insect mushroom body (MB) is a conserved brain structure that plays key roles in a diverse array of behaviors. The Drosophila melanogaster MB is the primary invertebrate model of neural circuits related to memory formation and storage, and its development, morphology, wiring, and function has been extensively studied. MBs consist of intrinsic Kenyon Cells that are divided into three major neuron classes (γ, α'/ß' and α/ß) and 7 cell subtypes (γd, γm, α'/ß'ap, α'/ß'm, α/ßp, α/ßs and α/ßc) based on their birth order, morphology, and connectivity. These subtypes play distinct roles in memory processing, however the underlying transcriptional differences are unknown. Here, we used RNA sequencing (RNA-seq) to profile the nuclear transcriptomes of each MB neuronal cell subtypes. We identified 350 MB class- or subtype-specific genes, including the widely used α/ß class marker Fas2 and the α'/ß' class marker trio Immunostaining corroborates the RNA-seq measurements at the protein level for several cases. Importantly, our data provide a full accounting of the neurotransmitter receptors, transporters, neurotransmitter biosynthetic enzymes, neuropeptides, and neuropeptide receptors expressed within each of these cell types. This high-quality, cell type-level transcriptome catalog for the Drosophila MB provides a valuable resource for the fly neuroscience community.


Assuntos
Linhagem da Célula/genética , Neurônios/metabolismo , Neuropeptídeos/genética , Transcriptoma/genética , Animais , Comportamento Animal , Encéfalo/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Drosophila melanogaster/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Corpos Pedunculados/metabolismo , Neurônios/classificação , Neuropeptídeos/metabolismo , Análise de Sequência de RNA
11.
Curr Opin Genet Dev ; 49: 95-105, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29705598

RESUMO

Like the famous Collyer's mansion in NY, our genomes have accumulated vast quantities of sequences that have been referred to as 'junk DNA,' much of which consists of retrotransposons (RTEs). A recent literature establishes the phenomenology that many RTEs become expressed at progressively higher levels during the course of normal aging. This seems to reflect gradual loss of heterochromatin in old age. In addition, RTEs appear to be precociously expressed in brains of younger animals that are experiencing neurodegenerative decline. Although it is difficult to distinguish cause from consequence, several recent studies support the contention that RTE expression, and even perhaps transposition, causally contribute to both the normal deterioration seen with age and to the precipitous decline in some neurodegenerative disorders. This may reflect a two hit model in which normal age-dependent loss of heterochromatin synergizes with a disruption to posttranscriptional silencing of RTEs caused by genetic and environmental stress.


Assuntos
Envelhecimento/genética , Heterocromatina/genética , Doenças Neurodegenerativas/genética , Retroelementos/genética , Envelhecimento/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Regulação da Expressão Gênica/genética , Genoma Humano/genética , Humanos , Doenças Neurodegenerativas/patologia
12.
PLoS Genet ; 13(3): e1006635, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28301478

RESUMO

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in response to hTDP-43 expression in glia versus neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD.


Assuntos
Proteínas de Ligação a DNA/genética , Modelos Animais de Doenças , Drosophila melanogaster/genética , Doenças Neurodegenerativas/genética , Retroelementos/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Animais , Animais Geneticamente Modificados , Proteínas de Ligação a DNA/metabolismo , Drosophila melanogaster/metabolismo , Drosophila melanogaster/ultraestrutura , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/metabolismo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Doenças Neurodegenerativas/metabolismo , Neuroglia/metabolismo , Neurônios/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa
13.
Cell Metab ; 25(1): 208-217, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28076762

RESUMO

Leptin, a typically adipose-derived "satiety hormone," has a well-established role in weight regulation. Here we describe a functionally conserved model of genetically induced obesity in Drosophila by manipulating the fly leptin analog unpaired 1 (upd1). Unexpectedly, cell-type-specific knockdown reveals upd1 in the brain, not the adipose tissue, mediates obesity-related traits. Disrupting brain-derived upd1 in flies leads to all the hallmarks of mammalian obesity: increased attraction to food cues, increased food intake, and increased weight. These effects are mediated by domeless receptors on neurons expressing Drosophila neuropeptide F, the orexigenic mammalian neuropeptide Y homolog. In vivo two-photon imaging reveals upd1 and domeless inhibit this hedonic signal in fed animals. Manipulations along this central circuit also create hypersensitivity to obesogenic conditions, emphasizing the critical interplay between biological predisposition and environment in overweight and obesity prevalence. We propose adipose- and brain-derived upd/leptin may control differing features of weight regulation through distinct neural circuits.


Assuntos
Comportamento Animal , Encéfalo/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Leptina/análogos & derivados , Rede Nervosa/metabolismo , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Animais , Peso Corporal , Drosophila melanogaster/efeitos dos fármacos , Comportamento Alimentar , Feminino , Técnicas de Silenciamento de Genes , Humanos , Odorantes , Fenótipo , Transdução de Sinais
15.
Mob DNA ; 5: 26, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-30117500

RESUMO

The Mobile Genetic Elements and Genome Evolution conference was hosted by Keystone Symposia in Santa Fe, NM USA, 9 March through 14 March 2014. The goal of this conference was to bring together scientists from around the world who study transposable elements in diverse organisms and researchers who study the impact these elements have on genome evolution. The meeting included over 200 scientists who participated through poster presentations, short talks selected from abstracts, and invited speakers. The talks were organized into eight sessions and two workshops. The topics varied from diverse mechanisms of mobilization to the evolution of genomes and their defense strategies against transposable elements.

16.
Nat Neurosci ; 16(5): 529-31, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23563579

RESUMO

We found that several transposable elements were highly active in Drosophila brain during normal aging. In addition, we found that mutations in Drosophila Argonaute 2 (Ago2) resulted in exacerbated transposon expression in the brain, progressive and age-dependent memory impairment, and shortened lifespan. These findings suggest that transposon activation may contribute to age-dependent loss of neuronal function.


Assuntos
Envelhecimento/fisiologia , Proteínas Argonautas/genética , Elementos de DNA Transponíveis/genética , Proteínas de Drosophila/genética , Drosophila/fisiologia , Longevidade/genética , Mutação/genética , Neurônios/fisiologia , Envelhecimento/genética , Análise de Variância , Animais , Animais Geneticamente Modificados , Aprendizagem da Esquiva/fisiologia , Encéfalo , Condicionamento Clássico/fisiologia , Drosophila/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo
17.
J Neurosci ; 33(13): 5821-33, 2013 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-23536094

RESUMO

MicroRNA (miRNA)-mediated gene regulation plays a key role in brain development and function. But there are few cases in which the roles of individual miRNAs have been elucidated in behaving animals. We report a miR-276a::DopR regulatory module in Drosophila that functions in distinct circuits for naive odor responses and conditioned odor memory. Drosophila olfactory aversive memory involves convergence of the odors (conditioned stimulus) and the electric shock (unconditioned stimulus) in mushroom body (MB) neurons. Dopamine receptor DopR mediates the unconditioned stimulus inputs onto MB. Distinct dopaminergic neurons also innervate ellipsoid body (EB), where DopR function modulates arousal to external stimuli. We demonstrate that miR-276a is required in MB neurons for memory formation and in EB for naive responses to odors. Both roles of miR-276a are mediated by tuning DopR expression. The dual role of this miR-276a::DopR genetic module in these two neural circuits highlights the importance of miRNA-mediated gene regulation within distinct circuits underlying both naive behavioral responses and memory.


Assuntos
Aprendizagem da Esquiva/fisiologia , MicroRNAs/metabolismo , Corpos Pedunculados/citologia , Neurônios/fisiologia , Condutos Olfatórios/citologia , Condutos Olfatórios/fisiologia , Análise de Variância , Animais , Animais Geneticamente Modificados , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Eletrochoque/efeitos adversos , Embrião não Mamífero/fisiologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas de Fluorescência Verde/genética , Temperatura Alta , Masculino , MicroRNAs/genética , Mutação/genética , Odorantes , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Curr Opin Neurobiol ; 23(1): 84-91, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23084099

RESUMO

From an information processing perspective, memories need to be acquired, encoded, stored, maintained and retrieved. As time passes after training, memories become less easily retrieved, but also become progressively more stable in the face of experimental perturbations. This process is referred to as consolidation. But the term has been used to describe two different biological processes whose relationship is poorly understood [1,2]. The first, which we refer to as biochemical consolidation, involves cell-signaling events within a neuron. The second, which we call systems consolidation, involves ongoing communication between brain regions or cell types. Although systems consolidation was first thought to be at play only in complex brains, a number of recent studies reveal its importance in Drosophila. The ease of cell type specific genetic manipulations in flies provides a unique opportunity to forge an integrated mechanistic understanding of biochemical and systems consolidation.


Assuntos
Encéfalo/fisiologia , Drosophila/fisiologia , Memória/fisiologia , Animais
19.
Neuron ; 76(2): 260-2, 2012 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-23083729

RESUMO

Memories are remarkably persistent, but rely on transient signaling. The prion-like properties of CPEB suggested a solution to this problem. The paper by Krüttner et al. (2012) in this issue of Neuron demonstrates that the prion-like domain of Drosophila CPEB functions independently of its RNA-binding domain for memory.

20.
PLoS One ; 7(9): e44099, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22957047

RESUMO

Elevated expression of specific transposable elements (TEs) has been observed in several neurodegenerative disorders. TEs also can be active during normal neurogenesis. By mining a series of deep sequencing datasets of protein-RNA interactions and of gene expression profiles, we uncovered extensive binding of TE transcripts to TDP-43, an RNA-binding protein central to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Second, we find that association between TDP-43 and many of its TE targets is reduced in FTLD patients. Third, we discovered that a large fraction of the TEs to which TDP-43 binds become de-repressed in mouse TDP-43 disease models. We propose the hypothesis that TE mis-regulation contributes to TDP-43 related neurodegenerative diseases.


Assuntos
Elementos de DNA Transponíveis , Proteínas de Ligação a DNA/genética , Doenças Neurodegenerativas/genética , Animais , Estudos de Casos e Controles , Lobo Frontal/patologia , Perfilação da Expressão Gênica , Genoma , Humanos , Camundongos , Modelos Estatísticos , Dados de Sequência Molecular , Neurônios/metabolismo , Ligação Proteica , RNA/metabolismo , Ratos
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