Sucrose-induced vacuolation results in increased expression of cholesterol biosynthesis and lysosomal genes

Helip-Wooley, Amanda; Thoene, Jess G.

doi:10.1016/j.yexcr.2003.09.003

Cited by 32 publications

(26 citation statements)

References 27 publications

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“…4C). The common disaccharide sucrose is known to activate TFEB and upregulate lysosomal-related genes in cell culture (Karageorgos et al, 1997;Helip-Wooley and Thoene, 2004;Sardiello et al, 2009). Trehalose, a disaccharide homologous to sucrose, has been recently reported to accelerate the clearance of mutant huntingtin and ␣-synuclein and to protect cultured neurons against mitochondria-dependent apoptotic insults by inducing autophagy (Sarkar et al, 2007).…”

Section: Enhancement Of Lysosomal Biogenesis In Mppmentioning

confidence: 99%

Pathogenic Lysosomal Depletion in Parkinson's Disease

Dehay¹,

Bové²,

et al. 2010

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Mounting evidence suggests a role for autophagy dysregulation in Parkinson's disease (PD). The bulk degradation of cytoplasmic proteins (including ␣-synuclein) and organelles (such as mitochondria) is mediated by macroautophagy, which involves the sequestration of cytosolic components into autophagosomes (AP) and its delivery to lysosomes. Accumulation of AP occurs in postmortem brain samples from PD patients, which has been widely attributed to an induction of autophagy. However, the cause and pathogenic significance of these changes remain unknown. Here we found in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of PD that AP accumulation and dopaminergic cell death are preceded by a marked decrease in the amount of lysosomes within dopaminergic neurons. Lysosomal depletion was secondary to the abnormal permeabilization of lysosomal membranes induced by increased mitochondrialderived reactive oxygen species. Lysosomal permeabilization resulted in a defective clearance and subsequent accumulation of undegraded AP and contributed directly to neurodegeneration by the ectopic release of lysosomal proteases into the cytosol. Lysosomal breakdown and AP accumulation also occurred in PD brain samples, where Lewy bodies were strongly immunoreactive for AP markers. Induction of lysosomal biogenesis by genetic or pharmacological activation of lysosomal transcription factor EB restored lysosomal levels, increased AP clearance and attenuated 1-methyl-4-phenylpyridinium-induced cell death. Similarly, the autophagy-enhancer compound rapamycin attenuated PD-related dopaminergic neurodegeneration, both in vitro and in vivo, by restoring lysosomal levels. Our results indicate that AP accumulation in PD results from defective lysosomal-mediated AP clearance secondary to lysosomal depletion. Restoration of lysosomal levels and function may thus represent a novel neuroprotective strategy in PD.

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Section: Enhancement Of Lysosomal Biogenesis In Mppmentioning

confidence: 99%

Pathogenic Lysosomal Depletion in Parkinson's Disease

Dehay¹,

Bové²,

et al. 2010

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“…Both Rab7L1 (27,28) and GAK (29,30) are reported to localize to the trans-Golgi network (TGN). WT Rab7L1 expressed alone (SI Appendix, Fig.…”

Section: Significancementioning

confidence: 99%

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

Beilina¹,

Rudenko²,

Kaganovich³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

336

383

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Significance Understanding loci nominated by genome-wide association studies (GWASs) is challenging. Here, we show, using the specific example of Parkinson disease, that identification of protein–protein interactions can help determine the most likely candidate for several GWAS loci. This result illustrates a significant general principle that will likely apply across multiple diseases.

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“…LTG-positive (acidic) organelle volume and pH, as well as cell volume and cytosolic pH, were measured at various time points, during a 4-h CQ incubation period (Table 1). Experiments were also performed in the presence of 0.1 M Suc, a treatment that perturbs endolysosomal membrane traffic and promotes a phospholipidosis-like phenotype (Helip-Wooley and Thoene, 2004). CQ uptake measurements were also performed in the presence of 10 nM Baf, a treatment that inhibits the phospholipidosis effect.…”

Section: Cq Uptake Is Coupled To Induction Of Phospholipidosis-like Pmentioning

confidence: 99%

“…Therefore, clinically relevant urine concentrations (0 -200 M) of CQ were used to mimic the physiological conditions of the distal tubule and used as input parameters to mathematically model transport behavior of CQ. Simulation results were compared with experimental measurements of intracellular CQ mass in dose-response and time course experiments, under conditions that either enhanced the phospholipidosis effect [cotreatment with sucrose (Wilson et al, 1987;Helip-Wooley and Thoene, 2004)] or inhibited vacuolation [cotreatment with bafilomycin A1 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

Zheng

Zhang

Rosania³

2010

J Pharmacol Exp Ther

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In vivo, the weakly basic, lipophilic drug chloroquine (CQ) accumulates in the kidney to concentrations more than a thousand-fold greater than those in plasma. To study the cellular pharmacokinetics of chloroquine in cells derived from the distal tubule, Madin-Darby canine kidney cells were incubated with CQ under various conditions. CQ progressively accumulated without exhibiting steady-state behavior. Experiments failed to yield evidence that known active transport mechanisms mediated CQ uptake at the plasma membrane. CQ induced a phospholipidosis-like phenotype, characterized by the appearance of numerous multivesicular and multilamellar bodies (MLBs/ MVBs) within the lumen of expanded cytoplasmic vesicles. Other induced phenotypic changes including changes in the volume and pH of acidic organelles were measured, and the integrated effects of all these changes were computationally modeled to establish their impact on intracellular CQ mass accumulation. Based on the passive transport behavior of CQ, the measured phenotypic changes fully accounted for the continuous, nonsteady-state CQ accumulation kinetics. Consistent with the simulation results, Raman confocal microscopy of live cells confirmed that CQ became highly concentrated within induced, expanded cytoplasmic vesicles that contained multiple MLBs/MVBs. Progressive CQ accumulation was increased by sucrose, a compound that stimulated the phospholipidosislike phenotype, and was decreased by bafilomycin A1, a compound that inhibited this phenotype. Thus, phospholipidosisassociated changes in organelle structure and intracellular membrane content can exert a major influence on the local bioaccumulation and biodistribution of drugs.

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Sucrose-induced vacuolation results in increased expression of cholesterol biosynthesis and lysosomal genes

Cited by 32 publications

References 27 publications

Pathogenic Lysosomal Depletion in Parkinson's Disease

Pathogenic Lysosomal Depletion in Parkinson's Disease

Unbiased screen for interactors of leucine-rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease

Effect of Phospholipidosis on the Cellular Pharmacokinetics of Chloroquine

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