Heat shock protein–based therapy as a potential candidate for treating the sphingolipidoses

Kirkegaard, Tove; Gray, James; Priestman, David A.; Wallom, Kerri L.; Atkins, Jennifer; Olsen, Ole Dines; Klein, Alexander; Drndarski, Svetlana; Petersen, Nikolaj H.T.; Ingemann, Linda; Smith, David A.; Morris, Lauren; Bornæs, Claus; Jørgensen, Signe Humle; Williams, Ian M.; Hinsby, Anders M.; Arenz, Christoph; Begley, David J.; Jäättelä, Marja; Platt, Frances M.

doi:10.1126/scitranslmed.aad9823

Cited by 155 publications

(168 citation statements)

References 113 publications

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“…Miglustat treatment delays the neurological progression of NPC patients but does not cure the disease, and has important side effects. Cholesterol reduction and moderate improvement in life span were achieved in NPC animal models by either activation of the heat-shock protein HSP70 with the drug arimoclomol [46] or administration of the cholesterol-sequestering drug b-cyclodextrin [36,[47][48][49]. Several compounds are currently being considered.…”

Section: Discussionmentioning

confidence: 99%

NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

et al. 2019

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NPC is a neurodegenerative disorder characterized by cholesterol accumulation in endolysosomal compartments. It is caused by mutations in the gene encoding NPC1, an endolysosomal protein mediating intracellular cholesterol trafficking. Cognitive and psychiatric alterations are hallmarks in NPC patients pointing to synaptic defects. However, the role of NPC1 in synapses has not been explored. We show that NPC1 is present in the postsynaptic compartment and is locally translated during LTP. A mutation in a region of the NPC1 gene commonly altered in NPC patients reduces NPC1 levels at synapses due to enhanced NPC1 protein degradation. This leads to shorter postsynaptic densities, increased synaptic cholesterol and impaired LTP in NPC1nmf164 mice with cognitive deficits. NPC1 mediates cholesterol mobilization and enables surface delivery of CYP46A1 and GluA1 receptors necessary for LTP, which is defective in NPC1nmf164 mice. Pharmacological activation of CYP46A1 normalizes synaptic levels of cholesterol, LTP and cognitive abilities, and extends life span of NPC1nmf164 mice. Our results unveil NPC1 as a regulator of cholesterol dynamics in synapses contributing to synaptic plasticity, and provide a potential therapeutic strategy for NPC patients.

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Section: Discussionmentioning

confidence: 99%

NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

et al. 2019

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“…High LBPA levels will alleviate cholesterol overload, which in turn will reduce storage and revert the cell response to the endosome overload, resulting in decreased levels of LBPA and other endosomal lipids and proteins. Since a very limited number of strategies only are emerging as possible treatment for NPC [31,43,51,52], we believe that our study of the FDA-approved compound thioperamide provides exciting novel perspectives for the treatment of NPC. In NPC mice, the effects of the drug are also likely to be masked by the beneficial decrease in storage of cholesterol and other lipids including LBPA.…”

Section: Discussionmentioning

confidence: 99%

Drug‐induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann–Pick type C cells and mice

et al. 2019

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Most cells acquire cholesterol by endocytosis of circulating low‐density lipoproteins (LDLs). After cholesteryl ester de‐esterification in endosomes, free cholesterol is redistributed to intracellular membranes via unclear mechanisms. Our previous work suggested that the unconventional phospholipid lysobisphosphatidic acid (LBPA) may play a role in modulating the cholesterol flux through endosomes. In this study, we used the Prestwick library of FDA‐approved compounds in a high‐content, image‐based screen of the endosomal lipids, lysobisphosphatidic acid and LDL‐derived cholesterol. We report that thioperamide maleate, an inverse agonist of the histamine H3 receptor HRH3, increases highly selectively the levels of lysobisphosphatidic acid, without affecting any endosomal protein or function that we tested. Our data also show that thioperamide significantly reduces the endosome cholesterol overload in fibroblasts from patients with the cholesterol storage disorder Niemann–Pick type C (NPC), as well as in liver of Npc1−/− mice. We conclude that LBPA controls endosomal cholesterol mobilization and export to cellular destinations, perhaps by fluidifying or buffering cholesterol in endosomal membranes, and that thioperamide has repurposing potential for the treatment of NPC.

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“…For example, cholesterol accumulation and lysosomal damage have been described in fibroblasts from PD patients carrying the N370S/wild‐type GBA1 mutation, and high sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann‐Pick disease type A patient fibroblasts . Protecting the lysosomal membrane by increasing the interaction between Hsp70 and the lipid BMP reverses lysosomal dysfunction in Niemann‐Pick disease …”

Section: Ldcd: Mechanism and Examplesmentioning

confidence: 99%

“…Exogenously administered recombinant Hsp70 (rHsp70) is efficiently endocytosed and accumulates in lysosomes, where it interacts with lipids on the intraluminal membrane and corrects the pathological changes in lysosomal morphology seen in primary fibroblasts from patients with both type A and B Niemann‐Pick disease . Like rHsp70, arimoclomol, a HSP‐modulating drug that acts as a coinducer of Hsp70, shows protective properties in several neurological mouse models of LSDs . In summary, Hsp70 and its coinducers are very promising therapies for LDS and neurodegenerative diseases.…”

Section: Lysosomes and Cell Death: Therapeutic Implicationsmentioning

confidence: 99%

Lysosomal membrane permeabilization and cell death

Wang

Gómez‐Sintes

Boya

2018

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Lysosomes are membrane-enclosed organelles that mediate the intracellular degradation of macromolecules. They play an essential role in calcium regulation and have emerged as key signaling hubs in controlling the nutrient response. Maintaining lysosomal integrity and function is therefore crucial for cellular homeostasis. Different forms of stress can induce lysosomal membrane permeabilization (LMP), resulting in the translocation to the cytoplasm of intralysosomal components, such as cathepsins, inducing lysosomal-dependent cell death (LDCD). Here, we review recent advances that have furthered our understanding of the molecular mechanisms of LMP and the methods used to detect it. We discuss several endolysosomal damage-response mechanisms that mediate the repair or elimination of compromised lysosomes and summarize the role of LMP and cathepsins in LDCD and other cell death pathways. Finally, with the emergence of lysosomes as promising therapeutic targets for several human diseases, we review a variety of therapeutic strategies that seek to either destabilize lysosomes or to maintain, enhance or restore lysosomal function.

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Heat shock protein–based therapy as a potential candidate for treating the sphingolipidoses

Cited by 155 publications

References 113 publications

NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

NPC 1 enables cholesterol mobilization during long‐term potentiation that can be restored in Niemann–Pick disease type C by CYP 46A1 activation

Drug‐induced increase in lysobisphosphatidic acid reduces the cholesterol overload in Niemann–Pick type C cells and mice

Lysosomal membrane permeabilization and cell death

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