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1.
Nature ; 613(7945): 696-703, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36450985

RESUMEN

In humans, traumatic social experiences can contribute to psychiatric disorders1. It is suggested that social trauma impairs brain reward function such that social behaviour is no longer rewarding, leading to severe social avoidance2,3. In rodents, the chronic social defeat stress (CSDS) model has been used to understand the neurobiology underlying stress susceptibility versus resilience following social trauma, yet little is known regarding its impact on social reward4,5. Here we show that, following CSDS, a subset of male and female mice, termed susceptible (SUS), avoid social interaction with non-aggressive, same-sex juvenile C57BL/6J mice and do not develop context-dependent social reward following encounters with them. Non-social stressors have no effect on social reward in either sex. Next, using whole-brain Fos mapping, in vivo Ca2+ imaging and whole-cell recordings, we identified a population of stress/threat-responsive lateral septum neurotensin (NTLS) neurons that are activated by juvenile social interactions only in SUS mice, but not in resilient or unstressed control mice. Optogenetic or chemogenetic manipulation of NTLS neurons and their downstream connections modulates social interaction and social reward. Together, these data suggest that previously rewarding social targets are possibly perceived as social threats in SUS mice, resulting from hyperactive NTLS neurons that occlude social reward processing.


Asunto(s)
Vías Nerviosas , Trauma Psicológico , Recompensa , Núcleos Septales , Conducta Social , Estrés Psicológico , Animales , Femenino , Masculino , Ratones , Encéfalo/patología , Encéfalo/fisiopatología , Calcio/análisis , Calcio/metabolismo , Ratones Endogámicos C57BL , Neuronas/metabolismo , Neurotensina/metabolismo , Optogenética , Trauma Psicológico/patología , Trauma Psicológico/fisiopatología , Núcleos Septales/patología , Núcleos Septales/fisiopatología , Estrés Psicológico/patología , Estrés Psicológico/fisiopatología
2.
Mol Cell ; 63(5): 781-95, 2016 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-27588602

RESUMEN

Mutations in the human autophagy gene EPG5 cause the multisystem disorder Vici syndrome. Here we demonstrated that EPG5 is a Rab7 effector that determines the fusion specificity of autophagosomes with late endosomes/lysosomes. EPG5 is recruited to late endosomes/lysosomes by direct interaction with Rab7 and the late endosomal/lysosomal R-SNARE VAMP7/8. EPG5 also binds to LC3/LGG-1 (mammalian and C. elegans Atg8 homolog, respectively) and to assembled STX17-SNAP29 Qabc SNARE complexes on autophagosomes. EPG5 stabilizes and facilitates the assembly of STX17-SNAP29-VAMP7/8 trans-SNARE complexes, and promotes STX17-SNAP29-VAMP7-mediated fusion of reconstituted proteoliposomes. Loss of EPG5 activity causes abnormal fusion of autophagosomes with various endocytic vesicles, in part due to elevated assembly of STX17-SNAP25-VAMP8 complexes. SNAP25 knockdown partially suppresses the autophagy defect caused by EPG5 depletion. Our study reveals that EPG5 is a Rab7 effector involved in autophagosome maturation, providing insight into the molecular mechanism underlying Vici syndrome.


Asunto(s)
Agenesia del Cuerpo Calloso/genética , Autofagosomas/metabolismo , Catarata/genética , Endosomas/metabolismo , Lisosomas/metabolismo , Proteínas/genética , Proteínas de Unión al GTP rab/genética , Agenesia del Cuerpo Calloso/metabolismo , Agenesia del Cuerpo Calloso/patología , Secuencia de Aminoácidos , Animales , Autofagosomas/ultraestructura , Autofagia/genética , Proteínas Relacionadas con la Autofagia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Catarata/metabolismo , Catarata/patología , Endosomas/ultraestructura , Regulación de la Expresión Génica , Células HeLa , Humanos , Proteínas de Membrana de los Lisosomas , Lisosomas/ultraestructura , Fusión de Membrana , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Unión Proteica , Proteínas/metabolismo , Proteínas Qa-SNARE/genética , Proteínas Qa-SNARE/metabolismo , Proteínas Qb-SNARE/genética , Proteínas Qb-SNARE/metabolismo , Proteínas Qc-SNARE/genética , Proteínas Qc-SNARE/metabolismo , Proteínas R-SNARE/genética , Proteínas R-SNARE/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Transducción de Señal , Proteína 25 Asociada a Sinaptosomas/genética , Proteína 25 Asociada a Sinaptosomas/metabolismo , Proteínas de Transporte Vesicular , Proteínas de Unión al GTP rab/metabolismo , Proteínas de Unión a GTP rab7
3.
J Cell Sci ; 132(19)2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31444285

RESUMEN

Vici syndrome is a severe and progressive multisystem disease caused by mutations in the EPG5 gene. In patient tissues and animal models, loss of EPG5 function is associated with defective autophagy caused by accumulation of non-degradative autolysosomes, but very little is known about the mechanism underlying this cellular phenotype. Here, we demonstrate that loss of function of the RBG-1-RBG-2 complex ameliorates the autophagy defect in C. elegansepg-5 mutants. The suppression effect is independent of the complex's activity as a RAB-3 GAP and a RAB-18 GEF. Loss of rbg-1 activity promotes lysosomal biogenesis and function, and also suppresses the accumulation of non-functional autolysosomes in epg-5 mutants. The mobility of late endosome- and lysosome-associated RAB-7 is reduced in epg-5 mutants, and this defect is rescued by simultaneous loss of function of rbg-1 Expression of the GDP-bound form of RAB-7 also promotes lysosomal biogenesis and suppresses the autophagy defect in epg-5 mutants. Our study reveals that the RBG-1-RBG-2 complex acts by modulating the dynamics of membrane-associated RAB-7 to regulate lysosomal biogenesis, and provides insights into the pathogenesis of Vici syndrome.


Asunto(s)
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas Portadoras/metabolismo , GTP Fosfohidrolasas/metabolismo , Lisosomas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Animales , Autofagia/genética , Autofagia/fisiología , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas Portadoras/genética , GTP Fosfohidrolasas/genética , Mutación/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Proteínas de Unión al GTP rab3/genética , Proteínas de Unión al GTP rab3/metabolismo
4.
Nat Chem Biol ; 14(8): 778-787, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29867141

RESUMEN

The mammalian Atg8 family proteins are central drivers of autophagy and contain six members, classified into the LC3 and GABARAP subfamilies. Due to their high sequence similarity and consequent functional overlaps, it is difficult to delineate specific functions of Atg8 proteins in autophagy. Here we discover a super-strong GABARAP-selective inhibitory peptide harbored in 270/480 kDa ankyrin-G and a super-potent pan-Atg8 inhibitory peptide from 440 kDa ankyrin-B. Structural studies elucidate the mechanism governing the Atg8 binding potency and selectivity of the peptides, reveal a general Atg8-binding sequence motif, and allow development of a more GABARAP-selective inhibitory peptide. These peptides effectively blocked autophagy when expressed in cultured cells. Expression of these ankyrin-derived peptides in Caenorhabditis elegans also inhibited autophagy, causing accumulation of the p62 homolog SQST-1, delayed development and shortened life span. Thus, these genetically encodable autophagy inhibitory peptides can be used to occlude autophagy spatiotemporally in living animals.


Asunto(s)
Ancirinas/química , Familia de las Proteínas 8 Relacionadas con la Autofagia/antagonistas & inhibidores , Autofagia/efectos de los fármacos , Péptidos/farmacología , Animales , Familia de las Proteínas 8 Relacionadas con la Autofagia/metabolismo , Células COS , Células Cultivadas , Chlorocebus aethiops , Péptidos/química
5.
Res Sq ; 2023 Jul 06.
Artículo en Inglés | MEDLINE | ID: mdl-37461537

RESUMEN

Aggression is an evolutionarily conserved behavior that controls social hierarchies and protects valuable resources like mates, food, and territory. In mice, aggressive behaviour can be broken down into an appetitive phase, which involves approach and investigation, and a consummatory phase, which involves biting, kicking, and wrestling. By performing an unsupervised weighted correlation network analysis on whole-brain c-Fos expression, we identified a cluster of brain regions including hypothalamic and amygdalar sub-regions and olfactory cortical regions highly co-activated in male, but not female aggressors (AGG). The posterolateral cortical amygdala (COApl), an extended olfactory structure, was found to be a hub region based on the number and strength of correlations with other regions in the cluster. Our data further show that estrogen receptor 1 (ESR1)-expressing cells in the COApl exhibit increased activity during attack behaviour, and during bouts of investigation which precede an attack, in male mice only. Chemogenetic or optogenetic inhibition of COApl ESR1 cells in AGG males reduces aggression and increases pro-social investigation without affecting social reward/reinforcement behavior. We further confirmed that COApl ESR1 projections to the ventrolateral portion of the ventromedial hypothalamus and central amygdala are necessary for these behaviours. Collectively, these data suggest that in aggressive males, COApl ESR1 cells respond specifically to social stimuli, thereby enhancing their salience and promoting attack behaviour.

6.
bioRxiv ; 2023 Aug 21.
Artículo en Inglés | MEDLINE | ID: mdl-37662400

RESUMEN

Chronic stress induces changes in the periphery and the central nervous system (CNS) that contribute to neuropathology and behavioral abnormalities associated with psychiatric disorders. In this study, we examined the impact of peripheral and central inflammation during chronic social defeat stress (CSDS) in female mice. Compared to male mice, we found that female mice exhibited heightened peripheral inflammatory response and identified C-C motif chemokine ligand 5 (CCL5), as a stress-susceptibility marker in females. Blocking CCL5 signaling in the periphery promoted resilience to CSDS. In the brain, stress-susceptible mice displayed increased expression of C-C chemokine receptor 5 (CCR5), a receptor for CCL5, in microglia in the prefrontal cortex (PFC). This upregulation was associated with microglia morphological changes, their increased migration to the blood vessels, and enhanced phagocytosis of synaptic components and vascular material. These changes coincided with neurophysiological alterations and impaired blood-brain barrier (BBB) integrity. By blocking CCR5 signaling specifically in the PFC were able to prevent stress-induced physiological changes and rescue social avoidance behavior. Our findings are the first to demonstrate that stress-mediated dysregulation of the CCL5-CCR5 axis triggers excessive phagocytosis of synaptic materials and neurovascular components by microglia, resulting in disruptions in neurotransmission, reduced BBB integrity, and increased stress susceptibility. Our study provides new insights into the role of cortical microglia in female stress susceptibility and suggests that the CCL5-CCR5 axis may serve as a novel sex-specific therapeutic target for treating psychiatric disorders in females.

7.
Res Sq ; 2023 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-37961128

RESUMEN

Chronic stress underlies the etiology of both major depressive disorder (MDD) and irritable bowel syndrome (IBS), two highly prevalent and debilitating conditions with high rates of co-morbidity. However, it is not fully understood how the brain and gut bi-directionally communicate during stress to impact intestinal homeostasis and stress-relevant behaviours. Using the chronic social defeat stress (CSDS) model, we find that stressed mice display greater intestinal permeability and circulating levels of the endotoxin lipopolysaccharide (LPS) compared to unstressed control (CON) mice. Interestingly, the microbiota in the colon also exhibit elevated LPS biosynthesis gene expression following CSDS. Additionally, CSDS triggers an increase in pro-inflammatory colonic IFNγ+ Th1 cells and a decrease in IL4+ Th2 cells compared to CON mice, and this gut inflammation contributes to stress-induced intestinal barrier permeability and social avoidance behaviour. We next investigated the role of enteric neurons and identified that noradrenergic dopamine beta-hydroxylase (DBH)+ neurons in the colon are activated by CSDS, and that their ablation protects against gut pathophysiology and disturbances in social behaviour. Retrograde tracing from the colon identified a population of corticotropin-releasing hormone-expressing (CRH+) neurons in the paraventricular nucleus of the hypothalamus (PVH) that innervate the colon and are activated by stress. Chemogenetically activating these PVH CRH+ neurons is sufficient to induce gut inflammation, barrier permeability, and social avoidance behaviour, while inhibiting these cells prevents these effects following exposure to CSDS. Thus, we define a stress-activated brain-to-gut circuit that confers colonic inflammation, leading to impaired intestinal barrier function, and consequent behavioural deficits.

8.
Front Aging Neurosci ; 14: 1019942, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36583187

RESUMEN

Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease affecting approximately 50 million people worldwide. It is estimated to reach 152 million by the year 2050. AD is the fifth leading cause of death among Americans age 65 and older. In spite of the significant burden the disease imposes upon patients, their families, our society, and our healthcare system, there is currently no cure for AD. The existing approved therapies only temporarily alleviate some of the disease's symptoms, but are unable to modulate the onset and/or progression of the disease. Our failure in developing a cure for AD is attributable, in part, to the multifactorial complexity underlying AD pathophysiology. Nonetheless, the lack of successful pharmacological approaches has led to the consideration of alternative strategies that may help delay the onset and progression of AD. There is increasing recognition that certain dietary and nutrition factors may play important roles in protecting against select key AD pathologies. Consistent with this, select nutraceuticals and phytochemical compounds have demonstrated anti-amyloidogenic, antioxidative, anti-inflammatory, and neurotrophic properties and as such, could serve as lead candidates for further novel AD therapeutic developments. Here we summarize some of the more promising dietary phytochemicals, particularly polyphenols that have been shown to positively modulate some of the important AD pathogenesis aspects, such as reducing ß-amyloid plaques and neurofibrillary tangles formation, AD-induced oxidative stress, neuroinflammation, and synapse loss. We also discuss the recent development of potential contribution of gut microbiome in dietary polyphenol function.

9.
Sci Rep ; 12(1): 3260, 2022 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-35228593

RESUMEN

Despite national and international efforts for the prevention of metabolic syndrome and its underlying diseases/disorders, its prevalence is still rising, especially in the middle-aged population. In this study, we explore the effect of high fat diet on the development of metabolic syndrome in middle-aged mice and to evaluate the potential benefits of voluntary physical exercise on the periphery as well as brain cognitive function, and to explore the potential mechanisms. We found that metabolic syndrome developed at middle age significantly impairs cognitive function and the impairment is associated with gene dysregulation in metabolic pathways that are largely affecting astrocytes in the brain. Eight-week voluntary wheel running at a frequency of three times a week, not only improves peripheral glucose control but also significantly improves learning and memory. The improvement of cognitive function is associated with restoration of gene expression involved in energy metabolism in the brain. Our study suggests that voluntary physical exercise is beneficial for metabolic syndrome-induced peripheral as well as cognitive dysfunction and can be recommended as therapeutic intervention for metabolic syndrome and associated diseases.


Asunto(s)
Síndrome Metabólico , Condicionamiento Físico Animal , Animales , Cognición , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Síndrome Metabólico/terapia , Ratones , Actividad Motora , Condicionamiento Físico Animal/fisiología
10.
Autophagy ; 16(4): 589-599, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-31204564

RESUMEN

Genetic screens have identified two sets of genes that act at distinct steps of basal autophagy in higher eukaryotes: the pan-eukaryotic ATG genes and the metazoan-specific EPG genes. Very little is known about whether these core macroautophagy/autophagy genes are differentially employed during multicellular organism development. Here we analyzed the function of core autophagy genes in autophagic removal of SQST-1/SQSTM1 during C. elegans development. We found that loss of function of genes acting at distinct steps in the autophagy pathway causes different patterns of SQST-1 accumulation in different tissues and developmental stages. We also identified that the calpain protease clp-2 acts in a cell context-specific manner in SQST-1 degradation. clp-2 is required for degradation of SQST-1 in the hypodermis and neurons, but is dispensable in the body wall muscle and intestine. Our results indicate that autophagy genes are differentially employed in a tissue- and stage-specific manner during the development of multicellular organisms.Abbreviations:ATG: autophagy related; CLP: calpain family; EPG: ectopic PGL granules; ER: endoplasmic reticulum; ESCRT: endosomal sorting complex required for transport; GFP: green fluorescent protein; LGG-1/LC3: LC3, GABARAP and GATE-16 family; MIT: microtubule interacting and transport; PGL: P granule abnormality protein; SQST-1: sequestosome-related; UPS: ubiquitin-proteasome system.


Asunto(s)
Autofagia/fisiología , Endosomas/metabolismo , Expresión Génica/fisiología , Macroautofagia/fisiología , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Lisosomas/metabolismo , Ubiquitina/metabolismo
11.
Mol Med Rep ; 9(5): 1648-52, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24626809

RESUMEN

XRCC4-like factor (XLF) is involved in non-homologous end joining-mediated repair of DNA double-strand breaks (DSBs). Mutations in the WRN gene results in the development of Werner syndrome (WS), a rare autosomal recessive disorder characterized by premature ageing and genome instability. In the present study, it was identified that XLF protein levels were lower in WRN-deficient fibroblasts, compared with normal fibroblasts. Depletion of WRN in HeLa cells led to a decrease of XLF mRNA and its promoter activity. Chromatin immunoprecipitation assays demonstrated that WRN was associated with the XLF promoter. Depletion of XLF in normal human fibroblasts increased the percentage of ß-galactosidase (ß-gal) staining-positive cells, indicating acceleration in cellular senescence. Taken together, the results suggest that XLF is a transcriptional target of WRN and may be involved in the regulation of cellular senescence.


Asunto(s)
Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Exodesoxirribonucleasas/metabolismo , Regulación de la Expresión Génica , RecQ Helicasas/metabolismo , Transcripción Genética , Línea Celular , Senescencia Celular/genética , Fibroblastos/metabolismo , Humanos , Regiones Promotoras Genéticas , Unión Proteica , Helicasa del Síndrome de Werner
12.
Eur J Med Chem ; 64: 401-9, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23665106

RESUMEN

A novel series of 4-substituted-piperazine-1-carbodithioate derivatives of 2,4-diaminoquinazoline were synthesized and tested for their antiproliferative activities against five human cancer cell lines including A549 (lung cancer), MCF-7 (breast adenocarcinoma), HeLa (cervical carcinoma), HT29 and HCT-116 (colorectal cancer). Most of the synthesized compounds showed broad spectrum antiproliferative activity (IC50 1.47-11.83 µM), of which 8f, 8m and 8q were the most active members with IC50 values in the range of 1.58-2.27, 1.84-3.27 and 1.47-4.68 µM against five cancer cell lines examined, respectively. Further investigations revealed that compounds 8f, 8m and 8q exhibited weak inhibition against dihydrofolate reductase and no activity against thymidylate synthase, while induced DNA damage and activated the G2/M checkpoint in HCT-116 cells.


Asunto(s)
Antineoplásicos/farmacología , Piperazinas/química , Quinazolinas/farmacología , Tiocarbamatos/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células HCT116 , Células HT29 , Células HeLa , Humanos , Células MCF-7 , Estructura Molecular , Quinazolinas/síntesis química , Quinazolinas/química , Relación Estructura-Actividad
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