2-Hydroxypropyl-β-cyclodextrin Promotes Transcription Factor EB-mediated Activation of Autophagy

Song, Wensi; Fan, Wei; Lotfi, Parisa; Sardiello, Marco; Segatori, Laura

doi:10.1074/jbc.m113.506246

Cited by 92 publications

(97 citation statements)

References 57 publications

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“…A predominantly nuclear localization of TFEB was observed in fibroblasts from mouse models of different lysosomal storage disorders, suggesting that the lysosome-autophagy system is modulated at the transcriptional level in response to lysosomal storage [11]. Modulation of TFEB activation was also observed upon cellular uptake of 2-hydroxypropyl-beta-cyclodextrin [12], quantum dots [13], and polystyrene nanoparticles [14], suggesting that transcriptional modulation of autophagy is part of the cellular adaptative response to nanomaterials.…”

Section: The Autophagy Pathwaymentioning

confidence: 82%

“…The ability of 2-hydroxypropyl-beta-cyclodextrin, an FDA-approved excipient used to enhance drug stability and bioavailability, to induce autophagic clearance was demonstrated in in vitro model systems characterized by aberrant accumulation of distinct biological materials [12,44]. Interestingly, 2-hydroxypropyl-beta-cyclodextrin-mediated activation of TFEB was found not to depend on its ability to alter cellular levels of cholesterol [44].…”

Section: Activation Of Autophagic Clearancementioning

confidence: 96%

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Differential autophagic responses to nano-sized materials

Popp

Segatori

2015

Current Opinion in Biotechnology

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Autophagy is a complex catabolic pathway that mediates degradation of excess or unwanted cytoplasmic components through the lysosome. Activated by environmental factors, such as nutrient depletion, and intracellular stimuli, such as proteotoxic stress, it provides a highly dynamic quality control mechanism to recycle cellular components, eliminate aberrant materials, and, ultimately, maintain cellular homeostasis. A growing body of evidence suggests that autophagy is also activated upon internalization of engineered nanomaterials, most likely as a protective response to what is perceived as foreign or toxic. This review describes the mechanisms of autophagy activation in response to naturally occurring and engineered nanomaterials. We provide a comprehensive analysis of the impact of nanomaterials on the lysosome-autophagy system, with particular emphasis on cellular markers associated with biocompatible and bioadverse outcomes of autophagy activation, such as clearance of toxic material and autophagy-associated cell death. Potential applications of the next-generation nanomaterials designed to interface with cellular clearance mechanisms with precisely tunable properties are also discussed.

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Section: The Autophagy Pathwaymentioning

confidence: 82%

Section: Activation Of Autophagic Clearancementioning

confidence: 96%

Differential autophagic responses to nano-sized materials

Popp

Segatori

2015

Current Opinion in Biotechnology

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“…Lysosome-related genes are reported to be closely regulated in the orbital fat of patients suffering from Graves' ophthalmopathy, whereas down-regulation of lysosomal processing improved pegylated lipopolyplex-mediated gene transfection (51,52). The increase in lysosomal biogenesis may not necessarily prove to be beneficial in all disease and cell types, but in some cases induction of the autophagy-lysosomal pathway could be helpful for cellular clearance of toxic wastes (53,54). Over the past few years, TFEB has emerged as a potential therapeutic target for some lysosome-related diseases.…”

Section: Discussionmentioning

confidence: 99%

“…However, not many therapeutically viable compounds targeting TFEB activity have been identified. Recently, it has been shown that 2-hydroxypropyl-␤-cyclodextrin, an FDA-approved excipient, promotes TFEB-mediated clearance of proteolipid aggregates in cells from patients suffering from LINCL (54). Another study reveals induction of TFEB levels and activity as well as lysosomal biogenesis by genistein (5,7-dihydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one), a potential drug for the use in substrate reduction therapy for mucopolysaccharidoses (60).…”

Section: Discussionmentioning

confidence: 99%

Activation of Peroxisome Proliferator-activated Receptor α Induces Lysosomal Biogenesis in Brain Cells

Ghosh

Jana

Modi

et al. 2015

Journal of Biological Chemistry

112

122

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“…Accordingly, it will be important to determine if βCDs trigger a transcriptional program that primes RPE cells to eliminate its lysosomal content, independently on whether they form soluble complex with the wasted material. Similarly, ibroblasts from patients with ceroid-lipofuscinosis, the most common cause of neurodegeneration of children in the United States, and cellular or animal models with misfolded α-synuclein accumulation were cleared by βCDs [132,133]. The mechanism in these cases seemed to be mediated by TFEB [86,134].…”

Section: Beta-cyclodextrins (β-Cds)mentioning

confidence: 99%

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

Nociari¹,

Kiss²,

Rodríguez-Boulan³

2017

Lysosomes - Associated Diseases and Methods to Study Their Function

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Photoreceptors undergo a constant renewal of their light sensitive outer segments (POSs). In the renewal process, 10% of the POS mass is daily phagocytized by the adjacent retinal pigment epithelium (RPE). POS contain vast amounts of 11-cis retinal and alltrans-retinal, two highly reactive vitamin A aldehydes that spontaneously dimerize into lipid bisretinoids (LBs) and accumulate into RPE lysosomes during phagocytosis. As LBs are refractory to lysosomal hydrolases and RPE cells do not divide, this accumulation is irreversible and results in the formation of lipofuscin granules. Lipofuscin accumulation is toxic for RPE cells through a variety of light-dependent and light-independent mechanisms. Beyond a threshold, RPE cells die resulting in secondary loss of overlying photoreceptors. Currently, there are no efective treatments for retinal disorders associated with genetic or age-associated LB accumulation, such as Stargardt disease and age-related macular degeneration (AMD). Thus, there is a great need for medical interventions. Here, we discuss the current understanding of lipofuscin's pathogenicity and the status of diferent strategies under development to promote LB elimination from RPE lysosomes.Keywords: lipofuscin, Stargardt, age-related macular degeneration (AMD), bisretinoids, retinal pigment epithelium (RPE), cyclodextrins, cellular clearance, TFEB, lysosome IntroductionTo understand the origin and consequences of the lysosomal accumulation of lipofuscin in the eye, a basic knowledge of retinal function and organization is required.© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The retinal pigment epithelium (RPE) in vertebrate's eyesLight entering the eye gets refracted by the cornea and lens on the neural retina, where photoreceptors (PR) convert photons into a cascade of chemical and electrical events that propagate to second-order (horizontal, bipolar, and amacrine cells) and third-order (ganglion cells) retinal neurons, which distribute this information to various visual centers of the brain through the ibers of the optic nerve. The bodies of PR cells, rods and cones, display three sectors (Figure 1): the outer segment, illed with stacks of disks densely packed with light-sensitive photopigment; the inner segment, illed with genetic, biosynthetic, and metabolic organelles Lysosomes -Associated Diseases and Methods to Study Their Function 4(nucleus, endoplasmic reticulum, Golgi complex, ribosomes, mitochondria); and the synaptic terminal that connects with bipolar neurons of the retina. In vertebrates, the retina is inverted in the sense that light passes through secondary and tertiary neuronal layers in the inner retina before reaching the rods and cones in the outer retina (Figure 1). Photoreceptors are metabolically very active cells that req...

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2-Hydroxypropyl-β-cyclodextrin Promotes Transcription Factor EB-mediated Activation of Autophagy

Cited by 92 publications

References 57 publications

Differential autophagic responses to nano-sized materials

Differential autophagic responses to nano-sized materials

Activation of Peroxisome Proliferator-activated Receptor α Induces Lysosomal Biogenesis in Brain Cells

Lipofuscin Accumulation into and Clearance from Retinal Pigment Epithelium Lysosomes: Physiopathology and Emerging Therapeutics

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