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1.
Traffic ; 23(5): 238-269, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35343629

RESUMEN

Since the discovery of lysosomes more than 70 years ago, much has been learned about the functions of these organelles. Lysosomes were regarded as exclusively degradative organelles, but more recent research has shown that they play essential roles in several other cellular functions, such as nutrient sensing, intracellular signalling and metabolism. Methodological advances played a key part in generating our current knowledge about the biology of this multifaceted organelle. In this review, we cover current methods used to analyze lysosome morphology, positioning, motility and function. We highlight the principles behind these methods, the methodological strategies and their advantages and limitations. To extract accurate information and avoid misinterpretations, we discuss the best strategies to identify lysosomes and assess their characteristics and functions. With this review, we aim to stimulate an increase in the quantity and quality of research on lysosomes and further ground-breaking discoveries on an organelle that continues to surprise and excite cell biologists.


Asunto(s)
Lisosomas , Redes y Vías Metabólicas , Lisosomas/metabolismo , Transducción de Señal
2.
EMBO J ; 39(8): e102468, 2020 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-32154600

RESUMEN

Vertebrate vision relies on the daily phagocytosis and lysosomal degradation of photoreceptor outer segments (POS) within the retinal pigment epithelium (RPE). However, how these events are controlled by light is largely unknown. Here, we show that the light-responsive miR-211 controls lysosomal biogenesis at the beginning of light-dark transitions in the RPE by targeting Ezrin, a cytoskeleton-associated protein essential for the regulation of calcium homeostasis. miR-211-mediated down-regulation of Ezrin leads to Ca2+ influx resulting in the activation of calcineurin, which in turn activates TFEB, the master regulator of lysosomal biogenesis. Light-mediated induction of lysosomal biogenesis and function is impaired in the RPE from miR-211-/- mice that show severely compromised vision. Pharmacological restoration of lysosomal biogenesis through Ezrin inhibition rescued the miR-211-/- phenotype, pointing to a new therapeutic target to counteract retinal degeneration associated with lysosomal dysfunction.


Asunto(s)
Calcio/metabolismo , Proteínas del Citoesqueleto/metabolismo , Regulación de la Expresión Génica , Lisosomas/metabolismo , MicroARNs/metabolismo , Animales , Autofagia , Proteínas del Citoesqueleto/antagonistas & inhibidores , Proteínas del Citoesqueleto/genética , Regulación hacia Abajo , Luz , Lisosomas/ultraestructura , Ratones , Ratones Noqueados , MicroARNs/genética , Fagocitosis , Fagosomas/metabolismo , Fagosomas/ultraestructura , Epitelio Pigmentado de la Retina/metabolismo
3.
Mol Ther ; 30(4): 1432-1450, 2022 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-35121108

RESUMEN

Mucopolysaccharidosis type IIIA (MPS-IIIA) is an autosomal recessive disorder caused by mutations in SGSH involved in the degradation of heparan sulfate. MPS-IIIA presents severe neurological symptoms such as progressive developmental delay and cognitive decline, for which there is currently no treatment. Brain targeting represents the main challenge for therapeutics to treat MPS-IIIA, and the development of small-molecule-based treatments able to reach the CNS could be a relevant advance for therapy. Using cell-based high content imaging to survey clinically approved drugs in MPS-IIIA cells, we identified fluoxetine, a selective serotonin reuptake inhibitor. Fluoxetine increases lysosomal and autophagic functions via TFEB activation through a RagC-dependent mechanism. Mechanistically, fluoxetine increases lysosomal exocytosis in mouse embryonic fibroblasts from MPS-IIIA mice, suggesting that this process may be responsible for heparan sulfate clearance. In vivo, fluoxetine ameliorates somatic and brain pathology in a mouse model of MPS-IIIA by decreasing the accumulation of glycosaminoglycans and aggregated autophagic substrates, reducing inflammation, and slowing down cognitive deterioration. We repurposed fluoxetine for potential therapeutics to treat human MPS-IIIA disease.


Asunto(s)
Mucopolisacaridosis III , Animales , Modelos Animales de Enfermedad , Fibroblastos/metabolismo , Fluoxetina/farmacología , Fluoxetina/uso terapéutico , Heparitina Sulfato/metabolismo , Hidrolasas/genética , Ratones , Mucopolisacaridosis III/tratamiento farmacológico , Mucopolisacaridosis III/genética
4.
Handb Exp Pharmacol ; 278: 109-126, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-35879578

RESUMEN

Ca2+ is a universal second messenger that plays a wide variety of fundamental roles in cellular physiology. Thus, to warrant selective responses and to allow rapid mobilization upon specific stimuli, Ca2+ is accumulated in organelles to keep it at very low levels in the cytoplasm during resting conditions. Major Ca2+ storage organelles include the endoplasmic reticulum (ER), the mitochondria, and as recently demonstrated, the lysosome (Xu and Ren, Annu Rev Physiol 77:57-80, 2015). The importance of Ca2+ signaling deregulation in human physiology is underscored by its involvement in several human diseases, including lysosomal storage disorders, neurodegenerative disease and cancer (Shen et al., Nat Commun 3:731, 2012; Bae et al., J Neurosci 34:11485-11503, 2014). Recent evidence strongly suggests that lysosomal Ca2+ plays a major role in the regulation of lysosomal adaptation to nutrient availability through a lysosomal signaling pathway involving the lysosomal Ca2+ channel TRPML1 and the transcription factor TFEB, a master regulator for lysosomal function and autophagy (Sardiello et al., Science 325:473-477, 2009; Settembre et al., Science 332:1429-1433, 2011; Medina et al., Nat Cell Biol 17:288-299, 2015; Di Paola et al., Cell Calcium 69:112-121, 2018). Due to the tight relationship of this lysosomal Ca2+ channel and TFEB, in this chapter, we will focus on the role of the TRPML1/TFEB pathway in the regulation of lysosomal function and autophagy.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Enfermedades Neurodegenerativas , Humanos , Autofagia , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Calcio/metabolismo , Regulación de la Expresión Génica , Lisosomas/metabolismo , Mitocondrias/metabolismo , Enfermedades Neurodegenerativas/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo
5.
Int J Mol Sci ; 22(23)2021 Nov 27.
Artículo en Inglés | MEDLINE | ID: mdl-34884638

RESUMEN

Diagnosis and cure for rare diseases represent a great challenge for the scientific community who often comes up against the complexity and heterogeneity of clinical picture associated to a high cost and time-consuming drug development processes. Here we show a drug repurposing strategy applied to nephropathic cystinosis, a rare inherited disorder belonging to the lysosomal storage diseases. This approach consists in combining mechanism-based and cell-based screenings, coupled with an affordable computational analysis, which could result very useful to predict therapeutic responses at both molecular and system levels. Then, we identified potential drugs and metabolic pathways relevant for the pathophysiology of nephropathic cystinosis by comparing gene-expression signature of drugs that share common mechanisms of action or that involve similar pathways with the disease gene-expression signature achieved with RNA-seq.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/genética , Cistinosis/tratamiento farmacológico , Cistinosis/genética , Reposicionamiento de Medicamentos , Enfermedades Renales/tratamiento farmacológico , Enfermedades Renales/genética , Enfermedades Raras/tratamiento farmacológico , Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Sistemas de Transporte de Aminoácidos Neutros/efectos de la radiación , Células Cultivadas , Biología Computacional/métodos , Cistinosis/metabolismo , Evaluación Preclínica de Medicamentos/métodos , Humanos , Enfermedades Renales/metabolismo , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Redes y Vías Metabólicas , Enfermedades Raras/genética , Enfermedades Raras/metabolismo , Transcriptoma
6.
EMBO J ; 29(21): 3607-20, 2010 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-20871593

RESUMEN

The function of lysosomes relies on the ability of the lysosomal membrane to fuse with several target membranes in the cell. It is known that in lysosomal storage disorders (LSDs), lysosomal accumulation of several types of substrates is associated with lysosomal dysfunction and impairment of endocytic membrane traffic. By analysing cells from two severe neurodegenerative LSDs, we observed that cholesterol abnormally accumulates in the endolysosomal membrane of LSD cells, thereby reducing the ability of lysosomes to efficiently fuse with endocytic and autophagic vesicles. Furthermore, we discovered that soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNAREs), which are key components of the cellular membrane fusion machinery are aberrantly sequestered in cholesterol-enriched regions of LSD endolysosomal membranes. This abnormal spatial organization locks SNAREs in complexes and impairs their sorting and recycling. Importantly, reducing membrane cholesterol levels in LSD cells restores normal SNARE function and efficient lysosomal fusion. Our results support a model by which cholesterol abnormalities determine lysosomal dysfunction and endocytic traffic jam in LSDs by impairing the membrane fusion machinery, thus suggesting new therapeutic targets for the treatment of these disorders.


Asunto(s)
Colesterol/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Lisosomas/metabolismo , Fusión de Membrana/fisiología , Proteínas SNARE/metabolismo , Animales , Autofagia , Western Blotting , Células Cultivadas , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Endocitosis/fisiología , Receptores ErbB/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Técnica del Anticuerpo Fluorescente , Técnicas para Inmunoenzimas , Inmunoprecipitación , Enfermedades por Almacenamiento Lisosomal/patología , Proteínas de Membrana de los Lisosomas/genética , Proteínas de Membrana de los Lisosomas/metabolismo , Ratones , Fosfolípidos/metabolismo , ARN Mensajero/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
7.
Cell Death Differ ; 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965447

RESUMEN

TFEB, a bHLH-leucine zipper transcription factor belonging to the MiT/TFE family, globally modulates cell metabolism by regulating autophagy and lysosomal functions. Remarkably, loss of TFEB in mice causes embryonic lethality due to severe defects in placentation associated with aberrant vascularization and resulting hypoxia. However, the molecular mechanism underlying this phenotype has remained elusive. By integrating in vivo analyses with multi-omics approaches and functional assays, we have uncovered an unprecedented function for TFEB in promoting the formation of a functional syncytiotrophoblast in the placenta. Our findings demonstrate that constitutive loss of TFEB in knock-out mice is associated with defective formation of the syncytiotrophoblast layer. Indeed, using in vitro models of syncytialization, we demonstrated that TFEB translocates into the nucleus during syncytiotrophoblast formation and binds to the promoters of crucial placental genes, including genes encoding fusogenic proteins (Syncytin-1 and Syncytin-2) and enzymes involved in steroidogenic pathways, such as CYP19A1, the rate-limiting enzyme for the synthesis of 17ß-Estradiol (E2). Conversely, TFEB depletion impairs both syncytial fusion and endocrine properties of syncytiotrophoblast, as demonstrated by a significant decrease in the secretion of placental hormones and E2 production. Notably, restoration of TFEB expression resets syncytiotrophoblast identity. Our findings identify that TFEB controls placental development and function by orchestrating both the transcriptional program underlying trophoblast fusion and the acquisition of endocrine function, which are crucial for the bioenergetic requirements of embryonic development.

8.
Nat Commun ; 14(1): 3911, 2023 07 03.
Artículo en Inglés | MEDLINE | ID: mdl-37400440

RESUMEN

Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3. Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease.


Asunto(s)
Glicoproteínas de Membrana , Lipofuscinosis Ceroideas Neuronales , Humanos , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Lipofuscinosis Ceroideas Neuronales/genética , Lipofuscinosis Ceroideas Neuronales/metabolismo , Receptor IGF Tipo 2/genética , Receptor IGF Tipo 2/metabolismo , Proteómica , Chaperonas Moleculares/metabolismo , Lisosomas/metabolismo , Hidrolasas/metabolismo , Autofagia
9.
EMBO Mol Med ; 13(11): e14434, 2021 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-34606154

RESUMEN

Pompe disease is a metabolic myopathy due to acid alpha-glucosidase deficiency. In addition to glycogen storage, secondary dysregulation of cellular functions, such as autophagy and oxidative stress, contributes to the disease pathophysiology. We have tested whether oxidative stress impacts on enzyme replacement therapy with recombinant human alpha-glucosidase (rhGAA), currently the standard of care for Pompe disease patients, and whether correction of oxidative stress may be beneficial for rhGAA therapy. We found elevated oxidative stress levels in tissues from the Pompe disease murine model and in patients' cells. In cells, stress levels inversely correlated with the ability of rhGAA to correct the enzymatic deficiency. Antioxidants (N-acetylcysteine, idebenone, resveratrol, edaravone) improved alpha-glucosidase activity in rhGAA-treated cells, enhanced enzyme processing, and improved mannose-6-phosphate receptor localization. When co-administered with rhGAA, antioxidants improved alpha-glucosidase activity in tissues from the Pompe disease mouse model. These results indicate that oxidative stress impacts on the efficacy of enzyme replacement therapy in Pompe disease and that manipulation of secondary abnormalities may represent a strategy to improve the efficacy of therapies for this disorder.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II , Animales , Terapia de Reemplazo Enzimático , Glucógeno/metabolismo , Enfermedad del Almacenamiento de Glucógeno Tipo II/tratamiento farmacológico , Humanos , Ratones , Estrés Oxidativo , alfa-Glucosidasas/metabolismo , alfa-Glucosidasas/uso terapéutico
10.
Biochim Biophys Acta Mol Basis Dis ; 1866(9): 165553, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-31521819

RESUMEN

Neuronal ceroid lipofuscinoses, also collectively known as Batten disease, are a group of rare monogenic disorders caused by mutations in at least 13 different genes. They are characterized by the accumulation of lysosomal storage material and progressive neurological deterioration with dementia, epilepsy, retinopathy, motor disturbances, and early death [1]. Although the identification of disease-causing genes provides an important step for understanding the molecular mechanisms underlying neuronal ceroid lipofuscinoses, compared to other diseases, obstacles to the development of therapies for these rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Current therapeutic strategies include enzyme replacement therapies, gene therapies targeting the brain and the eye, cell therapies, and pharmacological drugs that could modulate defective molecular pathways. In this review, we will focus in the emerging therapies based in the identification of small-molecules. Recent advances in high- throughput and high-content screening (HTS and HCS) using relevant cell-based assays and applying automation and imaging analysis algorithms, will allow the screening of a large number of compounds in lesser time. These approaches are particularly useful for drug repurposing for Batten disease, that takes the advantage to search for compounds that have already been tested in humans, thereby reducing significantly the resources needed for translation to clinics.


Asunto(s)
Lipofuscinosis Ceroideas Neuronales/tratamiento farmacológico , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Algoritmos , Animales , Humanos , Lisosomas/metabolismo , Lisosomas/patología , Mutación , Lipofuscinosis Ceroideas Neuronales/genética , Bibliotecas de Moléculas Pequeñas/química
11.
Cells ; 9(5)2020 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-32397616

RESUMEN

The MiT/TFE family of transcription factors (MITF, TFE3, and TFEB), which control transcriptional programs for autophagy and lysosome biogenesis have emerged as regulators of energy metabolism in cancer. Thus, their activation increases lysosomal catabolic function to sustain cancer cell growth and survival in stress conditions. Here, we found that TFEB depletion dramatically reduces basal expression levels of the cyclin-dependent kinase (CDK) inhibitor p21/WAF1 in various cell types. Conversely, TFEB overexpression increases p21 in a p53-dependent manner. Furthermore, induction of DNA damage using doxorubicin induces TFEB-mediated activation of p21, delays G2/M phase arrest, and promotes cell survival. Pharmacological inhibition of p21, instead, abrogates TFEB-mediated protection during the DNA damage response. Together, our findings uncover a novel and direct role of TFEB in the regulation of p21 expression in both steady-state conditions and during the induction of DNA-damage response (DDR). Our observations might open novel therapeutic strategies to promote cancer cell death by targeting the TFEB-p21 pathway in the presence of genotoxic agents.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Daño del ADN , Supervivencia Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/genética , Daño del ADN/genética , Fase G2 , Regulación de la Expresión Génica , Células HeLa , Humanos , Mitosis , Transcripción Genética , Proteína p53 Supresora de Tumor/metabolismo
12.
Cell Calcium ; 69: 112-121, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28689729

RESUMEN

Efficient functioning of lysosome is necessary to ensure the correct performance of a variety of intracellular processes such as degradation of cargoes coming from the endocytic and autophagic pathways, recycling of organelles, and signaling mechanisms involved in cellular adaptation to nutrient availability. Mutations in lysosomal genes lead to more than 50 lysosomal storage disorders (LSDs). Among them, mutations in the gene encoding TRPML1 (MCOLN1) cause Mucolipidosis type IV (MLIV), a recessive LSD characterized by neurodegeneration, psychomotor retardation, ophthalmologic defects and achlorhydria. At the cellular level, MLIV patient fibroblasts show enlargement and engulfment of the late endo-lysosomal compartment, autophagy impairment, and accumulation of lipids and glycosaminoglycans. TRPML1 is the most extensively studied member of a small family of genes that also includes TRPML2 and TRPML3, and it has been found to participate in vesicular trafficking, lipid and ion homeostasis, and autophagy. In this review we will provide an update on the latest and more novel findings related to the functions of TRPMLs, with particular focus on the emerging role of TRPML1 and lysosomal calcium signaling in autophagy. Moreover, we will also discuss new potential therapeutic approaches for MLIV and LSDs based on the modulation of TRPML1-mediated signaling.


Asunto(s)
Calcio/metabolismo , Lisosomas/metabolismo , Canales Catiónicos TRPM/metabolismo , Animales , Autofagia , Humanos , Terapia Molecular Dirigida , Mucolipidosis/metabolismo
13.
Nat Commun ; 9(1): 3312, 2018 08 17.
Artículo en Inglés | MEDLINE | ID: mdl-30120233

RESUMEN

During starvation the transcriptional activation of catabolic processes is induced by the nuclear translocation and consequent activation of transcription factor EB (TFEB), a master modulator of autophagy and lysosomal biogenesis. However, how TFEB is inactivated upon nutrient refeeding is currently unknown. Here we show that TFEB subcellular localization is dynamically controlled by its continuous shuttling between the cytosol and the nucleus, with the nuclear export representing a limiting step. TFEB nuclear export is mediated by CRM1 and is modulated by nutrient availability via mTOR-dependent hierarchical multisite phosphorylation of serines S142 and S138, which are localized in proximity of a nuclear export signal (NES). Our data on TFEB nucleo-cytoplasmic shuttling suggest an unpredicted role of mTOR in nuclear export.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Núcleo Celular/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Secuencia de Aminoácidos , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/química , Citosol/metabolismo , Células HEK293 , Células HeLa , Humanos , Carioferinas , Cinética , Fosforilación , Transporte de Proteínas , Receptores Citoplasmáticos y Nucleares , Proteína Exportina 1
14.
Hum Gene Ther ; 29(8): 886-901, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29641320

RESUMEN

Retinal gene therapy based on adeno-associated viral (AAV) vectors is safe and efficient in humans. The low intrinsic DNA transfer capacity of AAV has been expanded by dual vectors where a large expression cassette is split in two halves independently packaged in two AAV vectors. Dual AAV transduction efficiency, however, is greatly reduced compared to that obtained with a single vector. As AAV intracellular trafficking and processing are negatively affected by phosphorylation, this study set to identify kinase inhibitors that can increase dual AAV vector transduction. By high-throughput screening of a kinase inhibitors library, three compounds were identified that increase AAV transduction in vitro, one of which has a higher effect on dual than on single AAV vectors. Importantly, the transduction enhancement is exerted on various AAV serotypes and is not transgene dependent. As kinase inhibitors are promiscuous, siRNA-mediated silencing of targeted kinases was performed, and AURKA and B, PLK1, and PTK2 were among those involved in the increase of AAV transduction levels. The study shows that kinase inhibitor administration reduces AAV serotype 2 (AAV2) capsid phosphorylation and increases the activity of DNA-repair pathways involved in AAV DNA processing. Importantly, the kinase inhibitor PF-00562271 improves dual AAV8 transduction in photoreceptors following sub-retinal delivery in mice. The study identifies kinase inhibitors that increase dual and single AAV transduction by modulating AAV entry and post-entry steps.


Asunto(s)
Terapia Genética , Vectores Genéticos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/administración & dosificación , Retina/metabolismo , Transducción Genética , Animales , Aurora Quinasa A/antagonistas & inhibidores , Aurora Quinasa A/genética , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/genética , Dependovirus/genética , Quinasa 1 de Adhesión Focal/antagonistas & inhibidores , Quinasa 1 de Adhesión Focal/genética , Regulación de la Expresión Génica/efectos de los fármacos , Vectores Genéticos/uso terapéutico , Ensayos Analíticos de Alto Rendimiento , Humanos , Ratones , Células Fotorreceptoras/efectos de los fármacos , Células Fotorreceptoras/virología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/genética , Retina/patología , Retina/virología , Quinasa Tipo Polo 1
15.
Curr Drug Metab ; 18(12): 1147-1158, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28952432

RESUMEN

BACKGROUND: Lysosomotropic molecules are taken up into lysosomes in vitro and in vivo. Many drugs approved for clinical medicine are lysosomotropic agents, characterized by promoting particular effects including cytoplasmic vacuolization, increase in number and size of lysosomes, inhibition of their enzymes and accumulation of undegraded material, leading mainly to phospholipidosis. Despite lysosomotropism has been extensively described and studied, the pathophysiological significance of this process is still not well understood. Objetive: In this review, we focus on what is known about the effects of lysosomotropic drugs on specific lysosomal functions and their similarities with the phenotypic features of lysosomal storage disorders (LSDs). CONCLUSION: Some effects of lysosomotropic drugs are very similar to pathologic features of human genetic diseases affecting lysosomal function, and therefore these drugs can be used as tools to understand the mechanisms underlying such patho-pathways as well as to create pharmacologically-induced models of LSDs.


Asunto(s)
Enfermedades por Almacenamiento Lisosomal/patología , Lisosomas/efectos de los fármacos , Descubrimiento de Drogas , Humanos , Enfermedades por Almacenamiento Lisosomal/metabolismo , Lisosomas/metabolismo , Preparaciones Farmacéuticas
16.
Science ; 325(5939): 473-7, 2009 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-19556463

RESUMEN

Lysosomes are organelles central to degradation and recycling processes in animal cells. Whether lysosomal activity is coordinated to respond to cellular needs remains unclear. We found that most lysosomal genes exhibit coordinated transcriptional behavior and are regulated by the transcription factor EB (TFEB). Under aberrant lysosomal storage conditions, TFEB translocated from the cytoplasm to the nucleus, resulting in the activation of its target genes. TFEB overexpression in cultured cells induced lysosomal biogenesis and increased the degradation of complex molecules, such as glycosaminoglycans and the pathogenic protein that causes Huntington's disease. Thus, a genetic program controls lysosomal biogenesis and function, providing a potential therapeutic target to enhance cellular clearing in lysosomal storage disorders and neurodegenerative diseases.


Asunto(s)
Redes Reguladoras de Genes , Lisosomas/genética , Lisosomas/fisiología , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Células Cultivadas , Inmunoprecipitación de Cromatina , Secuencia de Consenso , Células HeLa , Humanos , Secuencias Invertidas Repetidas , Ratones , Regiones Promotoras Genéticas , Sacarosa/metabolismo , Factores de Transcripción/metabolismo
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