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1.
Neural Regen Res ; 19(5): 1006-1012, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-37862202

RESUMEN

Amyotrophic lateral sclerosis is a very disabling disease due to the degeneration of motor neurons. Symptoms include muscle weakness and atrophy, spasticity, and progressive paralysis. Currently, there is no treatment to reverse damage to motor neurons and cure amyotrophic lateral sclerosis. The only two treatments actually approved, riluzole and edaravone, have shown mitigated beneficial effects. The difficulty to find a cure lies in the complexity and multifaceted pattern of amyotrophic lateral sclerosis pathogenesis. Among mechanisms, abnormal RNA metabolism, nucleocytoplasmic transport defects, accumulation of unfolded protein, and mitochondrial dysfunction would in fine induce oxidative damage and vice versa. A potent therapeutic strategy will be to find molecules that break this vicious circle. Sharpening the nuclear factor erythroid-2 related factor 2 signaling may fulfill this objective since nuclear factor erythroid-2 related factor 2 has a multitarget profile controlling antioxidant defense, mitochondrial functioning, and inflammation. We here discuss the interest of developing nuclear factor erythroid-2 related factor 2-based therapy in regard to the pathophysiological mechanisms and we provide a general overview of the attempted clinical assays in amyotrophic lateral sclerosis.

2.
Redox Biol ; 58: 102542, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36442393

RESUMEN

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting upper and lower motor neurons. As a consequence, ALS patients display a locomotor disorder related to muscle weakness and progressive paralysis. Pathological mechanisms that participate in ALS involve deficient unfolded protein response, mitochondrial dysfunction and oxidative stress, among others. Finding a therapeutic target to break the vicious circle is particularly challenging. Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone that may be one of those targets. We here address and decipher the efficiency of S1R activation on a key ALS gene, TDP43, in zebrafish vertebrate model. While expression of mutant TDP43 (TDP43G348C) led to locomotor defects, treatment with the reference S1R agonist PRE-084 rescued motor performances in a zebrafish model. Treatment with the agonist ameliorated maximal mitochondrial respiration in the TDP43 context. We observed that TDP43G348C exacerbated ER stress induced by tunicamycin, resulting in increased levels of ER stress chaperone BiP and pro-apoptotic factor CHOP. Importantly, PRE-084 treatment in the same condition further heightened BiP levels but also EIF2α/ATF4 and NRF2 signalling cascades, both known to promote antioxidant protection during ER stress. Moreover, we showed that increasing NRF2 levels directly or by sulforaphane treatment rescued locomotor defects of TDP43G348C zebrafish. For the first time, we here provide the proof of concept that PRE-084 prevents mutant TDP43 toxicity by boosting ER stress response and antioxidant cascade through NRF2 signalling.


Asunto(s)
Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Animales , Pez Cebra/metabolismo , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Antioxidantes/uso terapéutico , Esclerosis Amiotrófica Lateral/genética , Proteínas de Unión al ADN/genética , Estrés del Retículo Endoplásmico , Receptor Sigma-1
3.
Front Mol Neurosci ; 12: 10, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30804750

RESUMEN

Parkinson's disease (PD) is a progressive CNS disorder that is primarily associated with impaired movement. PD develops over decades and is linked to the gradual loss of dopamine delivery to the striatum, via the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). While the administration of L-dopa and deep brain stimulation are potent therapies, their costs, side effects and gradual loss of efficacy underlines the need to develop other approaches. Unfortunately, the lack of pertinent animal models that reproduce DA neuron loss and behavior deficits-in a timeline that mimics PD progression-has hindered the identification of alternative therapies. A complementary approach to transgenic animals is the use of nonhuman primates (NHPs) combined with the overexpression of disease-related genes using viral vectors. This approach may induce phenotypes that are not influenced by developmental compensation mechanisms, and that take into account the personality of animals. In this review article, we discuss the combination of gene transfer and NHPs to develop "genetic" models of PD that are suitable for testing therapeutic approaches.

4.
Cell Death Dis ; 8(8): e3023, 2017 08 31.
Artículo en Inglés | MEDLINE | ID: mdl-29048426

RESUMEN

Neuroblastoma, a sympathetic nervous system tumor, accounts for 15% of cancer deaths in children. In contrast to most human tumors, p53 is rarely mutated in human primary neuroblastoma, suggesting impaired p53 activation in neuroblastoma. Various studies have shown correlations between fgf1 expression levels and both prognosis severity and tumor chemoresistance. As we previously showed that fibroblast growth factor 1 (FGF1) inhibited p53-dependent apoptosis in neuron-like PC12 cells, we initiated the study of the interaction between the FGF1 and p53 pathways in neuroblastoma. We focused on the activity of either extracellular FGF1 by adding recombinant rFGF1 in media, or of intracellular FGF1 by overexpression in human SH-SY5Y and mouse N2a neuroblastoma cell lines. In both cell lines, the genotoxic drug etoposide induced a classical mitochondrial p53-dependent apoptosis. FGF1 was able to inhibit p53-dependent apoptosis upstream of mitochondrial events in SH-SY5Y cells by both extracellular and intracellular pathways. Both rFGF1 addition and etoposide treatment increased fgf1 expression in SH-SY5Y cells. Conversely, rFGF1 or overexpressed FGF1 had no effect on p53-dependent apoptosis and fgf1 expression in neuroblastoma N2a cells. Using different FGF1 mutants (that is, FGF1K132E, FGF1S130A and FGF1S130D), we further showed that the C-terminal domain and phosphorylation of FGF1 regulate its intracrine anti-apoptotic activity in neuroblastoma SH-SY5Y cells. This study provides the first evidence for a role of an intracrine growth factor pathway on p53-dependent apoptosis in neuroblastoma, and could lead to the identification of key regulators involved in neuroblastoma tumor progression and chemoresistance.


Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Etopósido/farmacología , Factor 1 de Crecimiento de Fibroblastos/farmacología , Regulación Neoplásica de la Expresión Génica , Neuronas/efectos de los fármacos , Proteína p53 Supresora de Tumor/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Línea Celular Tumoral , Factor 1 de Crecimiento de Fibroblastos/genética , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Humanos , Ratones , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Mitocondrias/patología , Mutación , Neuronas/metabolismo , Neuronas/patología , Fosforilación/efectos de los fármacos , Dominios Proteicos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacología , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo
5.
Front Neurosci ; 9: 64, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25788873

RESUMEN

Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer's and prion diseases) or motor deficits (Parkinson's and related diseases).

6.
Mech Ageing Dev ; 130(8): 547-52, 2009 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-19486910

RESUMEN

The steroid hormone ecdysone influences Drosophila lifespan. Longevity is extended in mutants deficient for ecdysone synthesis or mutants of the ecdysone receptor (EcR). However, the underlying mechanisms remain unclear. Here we conditionally inactivated EcR by RNA interference or expression of dominant negative forms, using the RU486 inducible system. A mild ubiquitous inactivation of EcR during adulthood was sufficient to slow the aging of male flies, whereas a stronger EcR inactivation decreased longevity. Surprisingly, ubiquitous inactivation of EcR strongly decreased female lifespan. This deleterious effect was suppressed in sterile ovo(D1) mutant females, suggesting that EcR represses a negative signal for lifespan produced in ovaries. These results reveal a complex adult and sex-specific control of lifespan by steroid signalling in Drosophila.


Asunto(s)
Drosophila/fisiología , Regulación de la Expresión Génica , Longevidad , Receptores de Esteroides/fisiología , Animales , Femenino , Genes Dominantes , Masculino , Mifepristona/farmacología , Modelos Biológicos , Interferencia de ARN , Receptores de Esteroides/metabolismo , Factores Sexuales , Transducción de Señal , Esteroides/metabolismo
7.
Development ; 134(17): 3089-97, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17652353

RESUMEN

In recent decades, Drosophila mushroom bodies (MBs) have become a powerful model for elucidating the molecular mechanisms underlying brain development and function. We have previously characterized the derailed (drl; also known as linotte) receptor tyrosine kinase as an essential component of adult MB development. Here we show, using MARCM clones, a non-cell-autonomous requirement for the DRL receptor in MB development. This result is in accordance with the pattern of DRL expression, which occurs throughout development close to, but not inside, MB cells. While DRL expression can be detected within both interhemispheric glial and commissural neuronal cells, rescue of the drl MB defects appears to involve the latter cellular type. The WNT5 protein has been shown to act as a repulsive ligand for the DRL receptor in the embryonic central nervous system. We show here that WNT5 is required intrinsically within MB neurons for proper MB axonal growth and probably interacts with the extrinsic DRL receptor in order to stop axonal growth. We therefore propose that the neuronal requirement for both proteins defines an interacting network acting during MB development.


Asunto(s)
Proteínas de Drosophila/fisiología , Drosophila/embriología , Cuerpos Pedunculados/embriología , Proteínas Proto-Oncogénicas/fisiología , Proteínas Tirosina Quinasas Receptoras/fisiología , Proteínas Wnt/fisiología , Animales , Animales Modificados Genéticamente , Células Clonales/citología , Proteínas de Drosophila/genética , Embrión no Mamífero , Proteínas Tirosina Quinasas Receptoras/genética
8.
J Neurosci ; 27(10): 2483-92, 2007 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-17344386

RESUMEN

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the ataxin 7 (ATXN7) protein, a member of a multiprotein complex involved in histone acetylation. We have created a conditional Drosophila model of SCA7 in which expression of truncated ATXN7 (ATXN7T) with a pathogenic polyQ expansion is induced in neurons in adult flies. In this model, mutant ATXN7T accumulated in neuronal intranuclear inclusions containing ubiquitin, the 19S proteasome subunit, and HSP70 (heat shock protein 70), as in patients. Aggregation was accompanied by a decrease in locomotion and lifespan but limited neuronal death. Disaggregation of the inclusions, when expression of expanded ATXN7T was stopped, correlated with improved locomotor function and increased lifespan, suggesting that the pathology may respond to treatment. Lifespan was then used as a quantitative marker in a candidate gene approach to validate the interest of the model and to identify generic modulators of polyQ toxicity and specific modifiers of SCA7. Several molecular pathways identified in this focused screen (proteasome function, unfolded protein stress, caspase-dependent apoptosis, and histone acetylation) were further studied in primary neuronal cultures. Sodium butyrate, a histone deacetylase inhibitor, improved the survival time of the neurons. This model is therefore a powerful tool for studying SCA7 and for the development of potential therapies for polyQ diseases.


Asunto(s)
Modelos Animales de Enfermedad , Drosophila , Ataxias Espinocerebelosas/genética , Animales , Animales Modificados Genéticamente , Ataxina-7 , Muerte Celular , Células Cultivadas , Discinesias/genética , Glutamina , Humanos , Cuerpos de Inclusión Intranucleares/ultraestructura , Longevidad , Masculino , Mutación , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Péptidos/genética , Fenotipo , Ratas , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patología , Ataxias Espinocerebelosas/fisiopatología , Treonina
9.
Genes Cells ; 11(12): 1317-35, 2006 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-17121541

RESUMEN

In human, the myeloid leukemia factor 1 (hMLF1) has been shown to be involved in acute leukemia, and mlf related genes are present in many animals. Despite their extensive representation and their good conservation, very little is understood about their function. In Drosophila, dMLF physically interacts with both the transcription regulatory factor DREF and an antagonist of the Hedgehog pathway, Suppressor of Fused, whose over-expression in the fly suppresses the toxicity induced by polyglutamine. No connection between these data has, however, been established. Here, we show that dmlf is widely and dynamically expressed during fly development. We isolated and analyzed the first dmlf mutants: embryos lacking maternal dmlf product have a low viability with no specific defect, and dmlf(-)- adults display weak phenotypes. We monitored dMLF subcellular localization in the fly and cultured cells. We were able to show that, although generally nuclear, dMLF can also be cytoplasmic, depending on the developmental context. Furthermore, two differently spliced variants of dMLF display differential subcellular localization, allowing the identification of regions of dMLF potentially important for its localization. Finally, we demonstrate that dMLF can act developmentally and postdevelopmentally to suppress neurodegeneration and premature aging in a cerebellar ataxia model.


Asunto(s)
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila/embriología , Drosophila/genética , Empalme Alternativo , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , Núcleo Celular/metabolismo , Secuencia Conservada , Citoplasma/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/química , Embrión no Mamífero , Ojo/metabolismo , Ojo/ultraestructura , Regulación del Desarrollo de la Expresión Génica , Inmunohistoquímica , Datos de Secuencia Molecular , Mutación , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Represoras/metabolismo , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Fracciones Subcelulares/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
10.
BMC Genomics ; 7: 69, 2006 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-16584578

RESUMEN

BACKGROUND: During the last two decades progress in the genetics of aging in invertebrate models such as C. elegans and D. melanogaster has clearly demonstrated the existence of regulatory pathways that control the rate of aging in these organisms, such as the insulin-like pathway, the Jun kinase pathway and the Sir2 deacetylase pathway. Moreover, it was rapidly shown that some of these pathways are conserved from yeast to humans. In parallel to genetic studies, genomic expression approaches have given us significant information on the gene expression modifications that occur during aging either in wild type or long-lived mutant animals. But most of the genomic studies of invertebrate models have been performed so far on whole animals, while several recent studies in mammals have shown that the effects of aging are tissue specific. RESULTS: We used oligonucleotide microarrays to address the specificities of transcriptional responses in aging Drosophila in head, thorax or whole body. These fly parts are enriched in transcripts that represent different and complementary sets of genes. We present evidence for both specific and common transcriptional responses during the aging process in these tissues. About half of the genes described as downregulated with age are linked to reproduction and enriched in gonads. Greater downregulation of mitochondrial genes, activation of the JNK pathway and upregulation of proteasome subunits in the thorax of aged flies all suggest that muscle may be particularly sensitive to aging. Simultaneous age-related impairment of synaptic transmission gene expression is observed in fly heads. In addition, a detailed comparison with other microarray data indicates that in aged flies there are significant deviations from the canonical responses to oxidative stress and immune stress. CONCLUSION: Our data demonstrates the advantages and value of regionalized and comparative analysis of gene expression in aging animals. Adding to the age-regulated genes already identified in whole animal studies, it provides lists of new regionalized genes to be studied for their functional role in the aging process. This work also emphasizes the need for such experiments to reveal in greater detail the consequences of the transcriptional modifications induced by aging regulatory pathways.


Asunto(s)
Envejecimiento/genética , Drosophila melanogaster/genética , Regulación de la Expresión Génica , ARN Mensajero/genética , Transcripción Genética , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster/crecimiento & desarrollo , Femenino , Perfilación de la Expresión Génica , Cabeza/crecimiento & desarrollo , Masculino , Proteínas Musculares/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Especificidad de Órganos , Estrés Fisiológico/genética , Estrés Fisiológico/metabolismo , Transmisión Sináptica/genética , Tórax/crecimiento & desarrollo , Tórax/metabolismo
11.
C R Biol ; 328(1): 81-7, 2005 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-15714882

RESUMEN

In a fig-fig wasp symbiosis, we have discovered that male fig pollinators (Alfonsiella fimbriata Waterston) bite into the dehiscent anthers of Ficus natalensis leprieuri Miq., thus scattering the pollen grains throughout the syconium. Female pollinators are the only ones to transfer pollen to conspecific trees, and collect pollen actively from the anthers only. Thus, this male behaviour appears to be antagonistic to the pollination process. We compare different wasp pollinating behaviours between fig species exhibiting dehiscent and non-dehiscent anthers and conclude that this male behaviour is new and not required with spontaneously dehiscent anthers. These findings could suggest a host shift of Alfonsiella fimbriata.


Asunto(s)
Ficus/fisiología , Polen/fisiología , Avispas/fisiología , Animales , Ficus/clasificación , Ficus/parasitología , Interacciones Huésped-Parásitos , Simbiosis , Avispas/clasificación
12.
J Neurobiol ; 57(3): 291-302, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14608664

RESUMEN

Mushroom bodies (MB) are substructures in the Drosophila brain that are essential for memory. At present, MB anatomy is rather well described when compared to other brain areas, and elucidation of the genetic control of the development and projection patterns of MB neurons will be important to the understanding of their functions. We have performed a gain-of-function screen in order to identify genes that are involved in MB development. We drove expression of genes in MB neurons by crossing 2407 GAL4-driven UY element lines to lines containing an MB GAL4 source and UAS-GFP elements, and looked for defects in the MB structure. We have molecularly identified the genomic regions adjacent to the 26 positive UY insertions and found 18 potential genes that exhibit adult MB gain-of-function phenotypes. The proteins encoded by these candidate genes include, as well as genes with yet unknown function, transcription factors (e.g., tramtrack), nanos RNA-binding protein, microtubule-severing protein, vesicle trafficking proteins, axon guidance receptor, and the Src64 cytoplasmic protein tyrosine kinase. These genes are involved in key features of neuron cell biology. In three cases, tramtrack, nanos, and Src64, we show that the open reading frame located directly downstream of the UY P element is indeed the expressed target gene. Loss-of-function mutations of both ttk and Src64 lead to MB phenotypes proving that these genes are involved in the genetic control of MB development. Moreover, Src64 is shown here to act in a cell-autonomous fashion and is likely to interact with the previously-identified linotte/derailed receptor tyrosine kinase in MB development.


Asunto(s)
Proteínas de Drosophila , Drosophila/fisiología , Regulación de la Expresión Génica , Genes de Insecto , Cuerpos Pedunculados/fisiología , Proteínas Tirosina Quinasas/fisiología , Proteínas Proto-Oncogénicas , Animales , Microscopía Confocal , Mutación
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