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1.
EMBO Rep ; 24(2): e53801, 2023 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-36472244

RESUMO

Adult neural progenitor cells (aNPCs) ensure lifelong neurogenesis in the mammalian hippocampus. Proper regulation of aNPC fate has thus important implications for brain plasticity and healthy aging. Piwi proteins and the small noncoding RNAs interacting with them (piRNAs) have been proposed to control memory and anxiety, but the mechanism remains elusive. Here, we show that Piwil2 (Mili) is essential for proper neurogenesis in the postnatal mouse hippocampus. RNA sequencing of aNPCs and their differentiated progeny reveal that Mili and piRNAs are dynamically expressed in neurogenesis. Depletion of Mili and piRNAs in the adult hippocampus impairs aNPC differentiation toward a neural fate, induces senescence, and generates reactive glia. Transcripts modulated upon Mili depletion bear sequences complementary or homologous to piRNAs and include repetitive elements and mRNAs encoding essential proteins for proper neurogenesis. Our results provide evidence of a critical role for Mili in maintaining fitness and proper fate of aNPCs, underpinning a possible involvement of the piRNA pathway in brain plasticity and successful aging.


Assuntos
Proteínas Argonautas , Hipocampo , Neurogênese , Animais , Camundongos , Proteínas Argonautas/genética , Proteínas Argonautas/metabolismo , Senescência Celular/genética , Hipocampo/metabolismo , Mamíferos/genética , Mamíferos/metabolismo , Neurogênese/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo
2.
Cereb Cortex ; 34(1)2024 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-37997361

RESUMO

In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high γ oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high γ. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments.


Assuntos
Proteínas Serina-Treonina Quinases , Proteínas Tirosina Quinases , Animais , Camundongos , Modelos Animais de Doenças , Camundongos Transgênicos , Neurônios , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Células Piramidais
3.
Cell Mol Life Sci ; 78(5): 2081-2094, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33210214

RESUMO

Parkinson's disease (PD) is an incurable age-linked neurodegenerative disease with characteristic movement impairments that are caused by the progressive loss of dopamine-containing neurons (DAn) within the substantia nigra pars compacta. It has been suggested that misfolded protein aggregates together with neuroinflammation and glial reactivity, may impact nerve cell function, leading to neurodegeneration and diseases, such as PD. However, not many studies have been able to examine the role of human glial cells in the pathogenesis of PD. With the advent of induced pluripotent stem cell (iPSC) technology, it is now possible to reprogram human somatic cells to pluripotency and to generate viable human patient-specific DA neurons and glial cells, providing a tremendous opportunity for dissecting cellular and molecular pathological mechanisms occurring at early stages of PD. This reviews will report on recent work using human iPSC and 3D brain organoid models showing that iPSC technology can be used to recapitulate PD-relevant disease-associated phenotypes, including protein aggregation, cell death or loss of neurite complexity and deficient autophagic vacuoles clearance and focus on the recent co-culture systems that are revealing new insights into the complex interactions that occur between different brain cell types during neurodegeneration. Consequently, such advances are the key to improve our understanding of PD pathology and generate potential targets for new therapies aimed at curing PD patients.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Neuroglia/metabolismo , Doença de Parkinson/metabolismo , Animais , Astrócitos/citologia , Astrócitos/metabolismo , Técnicas de Cultura de Células/métodos , Neurônios Dopaminérgicos/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Neuroglia/citologia , Organoides/citologia , Organoides/metabolismo , Doença de Parkinson/patologia , Substância Negra/citologia , Substância Negra/metabolismo
4.
JCI Insight ; 9(3)2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38329129

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease associated with progressive death of midbrain dopamine (DAn) neurons in the substantia nigra (SN). Since it has been proposed that patients with PD exhibit an overall proinflammatory state, and since astrocytes are key mediators of the inflammation response in the brain, here we sought to address whether astrocyte-mediated inflammatory signaling could contribute to PD neuropathology. For this purpose, we generated astrocytes from induced pluripotent stem cells (iPSCs) representing patients with PD and healthy controls. Transcriptomic analyses identified a unique inflammatory gene expression signature in PD astrocytes compared with controls. In particular, the proinflammatory cytokine IL-6 was found to be highly expressed and released by PD astrocytes and was found to induce toxicity in DAn. Mechanistically, neuronal cell death was mediated by IL-6 receptor (IL-6R) expressed in human PD neurons, leading to downstream activation of STAT3. Blockage of IL-6R by the addition of the FDA-approved anti-IL-6R antibody, Tocilizumab, prevented PD neuronal death. SN neurons overexpressing IL-6R and reactive astrocytes expressing IL-6 were detected in postmortem brain tissue of patients at early stages of PD. Our findings highlight the potential role of astrocyte-mediated inflammatory signaling in neuronal loss in PD and pave the way for the design of future therapeutics.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Doença de Parkinson/metabolismo , Astrócitos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Interleucina-6/metabolismo , Doenças Neurodegenerativas/patologia , Neurônios Dopaminérgicos/metabolismo
5.
Neurobiol Dis ; 60: 18-31, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23969234

RESUMO

Hippocampal adult neurogenesis disruptions have been suggested as one of the neuronal plasticity mechanisms underlying learning and memory impairment in Down syndrome (DS). However, it remains unknown whether specific candidate genes are implicated in these phenotypes in the multifactorial context of DS. Here we report that transgenic mice (TgDyrk1A) with overdosage of Dyrk1A, a DS candidate gene, show important alterations in adult neurogenesis including reduced cell proliferation rate, altered cell cycle progression and reduced cell cycle exit leading to premature migration, differentiation and reduced survival of newly born cells. In addition, less proportion of newborn hippocampal TgDyrk1A neurons are activated upon learning, suggesting reduced integration in learning circuits. Some of these alterations were DYRK1A kinase-dependent since we could rescue those using a DYRK1A inhibitor, epigallocatechin-3-gallate. Environmental enrichment also normalized DYRK1A kinase overdosage in the hippocampus, and rescued adult neurogenesis alterations in TgDyrk1A mice. We conclude that Dyrk1A is a good candidate to explain neuronal plasticity deficits in DS and that normalizing the excess of DYRK1A kinase activity either pharmacologically or using environmental stimulation can correct adult neurogenesis defects in DS.


Assuntos
Meio Ambiente , Hipocampo/enzimologia , Neurogênese , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Síndrome de Down/enzimologia , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Proteínas Serina-Treonina Quinases/genética , Proteínas Tirosina Quinases/genética , Quinases Dyrk
6.
Amino Acids ; 45(1): 113-31, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23604404

RESUMO

The development of strategies capable to promote nervous system plasticity in adulthood is nowadays an important aim in neuroscience to improve not only cognitive abilities but also to ameliorate pathological dysfunctions. Several studies have demonstrated that adult neurogenesis is regulated by many physiological and pathological stimuli at almost every stage, from proliferation of neuronal precursors until integration and activation of newly formed neurons in the preexisting network. We review the process of generating functional neurons from precursors in the adult brain and its implications in intellectual disability disorders.


Assuntos
Encéfalo/fisiologia , Hipocampo/fisiologia , Deficiência Intelectual/fisiopatologia , Neurogênese , Animais , Diferenciação Celular , Humanos , Camundongos , Neurônios/fisiologia
7.
bioRxiv ; 2023 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-36945607

RESUMO

Abnormal dendritic arbors, dendritic spine "dysgenesis" and excitation inhibition imbalance are main traits assumed to underlie impaired cognition and behavioral adaptation in intellectual disability. However, how these modifications actually contribute to functional properties of neuronal networks, such as signal integration or storage capacity is unknown. Here, we used a mouse model overexpressing Dyrk1A (Dual-specificity tyrosine [Y]-regulated kinase), one of the most relevant Down syndrome (DS) candidate genes, to gather quantitative data regarding hippocampal neuronal deficits produced by the overexpression of Dyrk1A in mice (TgDyrk1A; TG). TG mice showed impaired hippocampal recognition memory, altered excitation-inhibition balance and deficits in hippocampal CA1 LTP. We also detected for the first time that deficits in dendritic arborization in TG CA1 pyramidal neurons are layer-specific, with a reduction in the width of the stratum radiatum, the postsynaptic target site of CA3 excitatory neurons, but not in the stratum lacunosum-moleculare, which receives temporo-ammonic projections. To interrogate about the functional impact of layer-specific TG dendritic deficits we developed tailored computational multicompartmental models. Computational modelling revealed that neuronal microarchitecture alterations in TG mice lead to deficits in storage capacity, altered the integration of inputs from entorhinal cortex and hippocampal CA3 region onto CA1 pyramidal cells, important for coding place and temporal context and on connectivity and activity dynamics, with impaired the ability to reach high γ oscillations. Contrary to what is assumed in the field, the reduced network activity in TG is mainly contributed by the deficits in neuronal architecture and to a lesser extent by over-inhibition. Finally, given that therapies aimed at improving cognition have also been tested for their capability to recover dendritic spine deficits and excitation-inhibition imbalance, we also tested the short- and long-term changes produced by exposure to environmental enrichment (EE). Exposure to EE normalized the excitation inhibition imbalance and LTP, and had beneficial effects on short-term recognition memory. Importantly, it produced massive but transient dendritic remodeling of hippocampal CA1, that led to recovery of high γ oscillations, the main readout of synchronization of CA1 neurons, in our simulations. However, those effects where not stable and were lost after EE discontinuation. We conclude that layer-specific neuromorphological disturbances produced by Dyrk1A overexpression impair coding place and temporal context. Our results also suggest that treatments targeting structural plasticity, such as EE, even though hold promise towards improved treatment of intellectual disabilities, only produce temporary recovery, due to transient dendritic remodeling.

8.
EMBO Mol Med ; 15(3): e15847, 2023 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-36740977

RESUMO

Tyrosine hydroxylase deficiency (THD) is a rare genetic disorder leading to dopaminergic depletion and early-onset Parkinsonism. Affected children present with either a severe form that does not respond to L-Dopa treatment (THD-B) or a milder L-Dopa responsive form (THD-A). We generated induced pluripotent stem cells (iPSCs) from THD patients that were differentiated into dopaminergic neurons (DAn) and compared with control-DAn from healthy individuals and gene-corrected isogenic controls. Consistent with patients, THD iPSC-DAn displayed lower levels of DA metabolites and reduced TH expression, when compared to controls. Moreover, THD iPSC-DAn showed abnormal morphology, including reduced total neurite length and neurite arborization defects, which were not evident in DAn differentiated from control-iPSC. Treatment of THD-iPSC-DAn with L-Dopa rescued the neuronal defects and disease phenotype only in THDA-DAn. Interestingly, L-Dopa treatment at the stage of neuronal precursors could prevent the alterations in THDB-iPSC-DAn, thus suggesting the existence of a critical developmental window in THD. Our iPSC-based model recapitulates THD disease phenotypes and response to treatment, representing a promising tool for investigating pathogenic mechanisms, drug screening, and personalized management.


Assuntos
Células-Tronco Pluripotentes Induzidas , Levodopa , Neurônios Dopaminérgicos/metabolismo , Células-Tronco Pluripotentes Induzidas/metabolismo , Levodopa/uso terapêutico , Levodopa/metabolismo , Fenótipo , Humanos
9.
Front Mol Neurosci ; 14: 664912, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34025350

RESUMO

In early development, the environment triggers mnemonic epigenomic programs resulting in memory and learning experiences to confer cognitive phenotypes into adulthood. To uncover how environmental stimulation impacts the epigenome and genome organization, we used the paradigm of environmental enrichment (EE) in young mice constantly receiving novel stimulation. We profiled epigenome and chromatin architecture in whole cortex and sorted neurons by deep-sequencing techniques. Specifically, we studied chromatin accessibility, gene and protein regulation, and 3D genome conformation, combined with predicted enhancer and chromatin interactions. We identified increased chromatin accessibility, transcription factor binding including CTCF-mediated insulation, differential occupancy of H3K36me3 and H3K79me2, and changes in transcriptional programs required for neuronal development. EE stimuli led to local genome re-organization by inducing increased contacts between chromosomes 7 and 17 (inter-chromosomal). Our findings support the notion that EE-induced learning and memory processes are directly associated with the epigenome and genome organization.

10.
Stem Cell Reports ; 12(6): 1298-1312, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31130358

RESUMO

Physical exercise stimulates adult hippocampal neurogenesis and is considered a relevant strategy for preventing age-related cognitive decline in humans. The underlying mechanisms remains controversial. Here, we show that exercise increases proliferation of neural precursor cells (NPCs) of the mouse dentate gyrus (DG) via downregulation of microRNA 135a-5p (miR-135a). MiR-135a inhibition stimulates NPC proliferation leading to increased neurogenesis, but not astrogliogenesis, in DG of resting mice, and intriguingly it re-activates NPC proliferation in aged mice. We identify 17 proteins (11 putative targets) modulated by miR-135 in NPCs. Of note, inositol 1,4,5-trisphosphate (IP3) receptor 1 and inositol polyphosphate-4-phosphatase type I are among the modulated proteins, suggesting that IP3 signaling may act downstream miR-135. miR-135 is the first noncoding RNA essential modulator of the brain's response to physical exercise. Prospectively, the miR-135-IP3 axis might represent a novel target of therapeutic intervention to prevent pathological brain aging.


Assuntos
Células-Tronco Adultas/metabolismo , Envelhecimento/metabolismo , MicroRNAs/biossíntese , Células-Tronco Neurais/metabolismo , Neurogênese , Condicionamento Físico Animal , Animais , Proliferação de Células , Regulação da Expressão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Ventrículos Laterais/citologia , Ventrículos Laterais/metabolismo , Camundongos , Camundongos Knockout , Nicho de Células-Tronco , Proteínas Quinases p38 Ativadas por Mitógeno/biossíntese
11.
Stem Cell Reports ; 12(2): 213-229, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30639209

RESUMO

Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.


Assuntos
Astrócitos/citologia , Células-Tronco Pluripotentes Induzidas/citologia , Doença de Parkinson/fisiopatologia , Astrócitos/metabolismo , Autofagia/fisiologia , Diferenciação Celular/fisiologia , Células Cultivadas , Técnicas de Cocultura/métodos , Neurônios Dopaminérgicos/citologia , Neurônios Dopaminérgicos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Mesencéfalo/citologia , Mesencéfalo/metabolismo , Neuroglia , Doença de Parkinson/metabolismo , Fenótipo , alfa-Sinucleína/metabolismo
12.
Front Mol Neurosci ; 11: 415, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30498432

RESUMO

Using a lentivirus-mediated labeling method, we investigated whether the adult hippocampus retains long-lasting, self-renewing neural stem cells (NSCs). We first showed that a single injection of a lentiviral vector expressing a green fluorescent protein (LV PGK-GFP) into the subgranular zone (SGZ) of the adult hippocampus enabled an efficient, robust, and long-term marking of self-renewing NSCs and their progeny. Interestingly, a subset of labeled cells showed the ability to proliferate multiple times and give rise to Sox2+ cells, clearly suggesting the ability of NSCs to self-renew for an extensive period of time (up to 6 months). In addition, using GFP+ cells isolated from the SGZ of mice that received a LV PGK-GFP injection 3 months earlier, we demonstrated that some GFP+ cells displayed the essential properties of NSCs, such as self-renewal and multipotency. Furthermore, we investigated the plasticity of NSCs in a perforant path transection, which has been shown to induce astrocyte formation in the molecular layer of the hippocampus. Our lentivirus (LV)-mediated labeling study revealed that hippocampal NSCs are not responsible for the burst of astrocyte formation, suggesting that signals released from the injured perforant path did not influence NSC fate determination. Therefore, our studies showed that a gene delivery system using LVs is a unique method to be used for understanding the complex nature of NSCs and may have translational impact in gene therapy by efficiently targeting NSCs.

13.
Nat Commun ; 8: 14336, 2017 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-28186121

RESUMO

Circadian rhythms are controlled by a network of clock neurons in the central pacemaker, the suprachiasmatic nucleus (SCN). Core clock genes, such as Bmal1, are expressed in SCN neurons and in other brain cells, such as astrocytes. However, the role of astrocytic clock genes in controlling rhythmic behaviour is unknown. Here we show that ablation of Bmal1 in GLAST-positive astrocytes alters circadian locomotor behaviour and cognition in mice. Specifically, deletion of astrocytic Bmal1 has an impact on the neuronal clock through GABA signalling. Importantly, pharmacological modulation of GABAA-receptor signalling completely rescues the behavioural phenotypes. Our results reveal a crucial role of astrocytic Bmal1 for the coordination of neuronal clocks and propose a new cellular target, astrocytes, for neuropharmacology of transient or chronic perturbation of circadian rhythms, where alteration of astrocytic clock genes might contribute to the impairment of the neurobehavioural outputs such as cognition.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Astrócitos/metabolismo , Cognição/fisiologia , Atividade Motora/fisiologia , Ácido gama-Aminobutírico/metabolismo , Fatores de Transcrição ARNTL/genética , Animais , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Camundongos Knockout , Atividade Motora/genética , Neurônios/metabolismo , Deleção de Sequência , Transdução de Sinais , Núcleo Supraquiasmático/citologia , Núcleo Supraquiasmático/metabolismo , Núcleo Supraquiasmático/fisiologia
14.
Stem Cell Reports ; 8(4): 1046-1061, 2017 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-28330621

RESUMO

Adult neurogenesis requires the precise control of neuronal versus astrocyte lineage determination in neural stem cells. While microRNAs (miRNAs) are critically involved in this step during development, their actions in adult hippocampal neural stem cells (aNSCs) has been unclear. As entry point to address that question we chose DICER, an endoribonuclease essential for miRNA biogenesis and other RNAi-related processes. By specific ablation of Dicer in aNSCs in vivo and in vitro, we demonstrate that miRNAs are required for the generation of new neurons, but not astrocytes, in the adult murine hippocampus. Moreover, we identify 11 miRNAs, of which 9 have not been previously characterized in neurogenesis, that determine neurogenic lineage fate choice of aNSCs at the expense of astrogliogenesis. Finally, we propose that the 11 miRNAs sustain adult hippocampal neurogenesis through synergistic modulation of 26 putative targets from different pathways.


Assuntos
Células-Tronco Adultas/citologia , MicroRNAs/genética , Células-Tronco Neurais/citologia , Neurogênese , Neurônios/citologia , Células-Tronco Adultas/metabolismo , Animais , Células Cultivadas , RNA Helicases DEAD-box/genética , Deleção de Genes , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Células-Tronco Neurais/metabolismo , Neurônios/metabolismo , Ribonuclease III/genética
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