Mechanistic convergence and shared therapeutic targets in Niemann‐Pick disease

Colaço, Alexandria; Kaya, Ecem; Adriaenssens, Elias; Davis, Lianne C.; Zampieri, Stefania; Fernández-Suárez, María E.; Tan, Chong Yew; Deegan, Patrick; Porter, Forbes D.; Galione, Antony; Bembi, Bruno; Dardis, Andrea; Platt, Frances M.

doi:10.1002/jimd.12191

Cited by 13 publications

(10 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Very significantly Tangier disease has recently been found to share cell biological and biochemical features of NPC disease, including reduced lysosomal Ca 2+ storage. Additionally, one patient with Tangier disease treated with miglustat showed a clinical response to this NPC therapeutic suggesting pathogenic convergence 38,39 . Collagen and thrombin induced aggregation defects were also observed in a mouse model of Tangier disease and individuals with Tangier disease, suggesting agonists‐mediated platelet activation signaling defects in Tangier disease 37 …”

Section: Discussionmentioning

confidence: 96%

Defective platelet function in Niemann‐Pick disease type C1

et al. 2020

Self Cite

View full text Add to dashboard Cite

Niemann‐Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder caused by mutations in either NPC1 (95% of cases) or NPC2. Reduced late endosome/lysosome calcium (Ca2+) levels and the accumulation of unesterified cholesterol and sphingolipids within the late endocytic system characterize this disease. We previously reported impaired lysosome‐related organelle (LRO) function in Npc1−/− Natural Killer cells; however, the potential contribution of impaired acid compartment Ca2+ flux and LRO function in other cell types has not been determined. Here, we investigated LRO function in NPC1 disease platelets. We found elevated numbers of circulating platelets, impaired platelet aggregation and prolonged bleeding times in a murine model of NPC1 disease. Electron microscopy revealed abnormal ultrastructure in murine platelets, consistent with that seen in a U18666A (pharmacological inhibitor of NPC1) treated megakaryocyte cell line (MEG‐01) exhibiting lipid storage and acidic compartment Ca2+ flux defects. Furthermore, platelets from NPC1 patients across different ages were found to cluster at the lower end of the normal range when platelet numbers were measured and had platelet volumes that were clustered at the top of the normal range. Taken together, these findings highlight the role of acid compartment Ca2+ flux in the function of platelet LROs.

show abstract

Section: Discussionmentioning

confidence: 96%

Defective platelet function in Niemann‐Pick disease type C1

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…L-Leucine not only serves as a building block for protein synthesis but is also a potent activator of the mammalian target of rapamycin (mTOR), involved in many cellular processes, including protein synthesis, nutrient sensing, cell growth, metabolism, and glucose, lipid and glutamate utilisation [26,34,38]. In this study, we explored the modified leucine amino acid, ADLL, for its potential therapeutic effects in a mouse model of Sandhoff disease, as it had previously provided beneficial effects in another lysosomal storage disease, NPC1 (observational clinical study) [16] and in Tangier disease patient cells [17]. Here, we found that ADLL modestly but significantly extended lifespan and significantly slowed disease progression in Hexb -/mice.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, cognitive improvements were anecdotally reported by parents of some NPC1 patients who received ADLL treatment, suggesting potential functional benefit beyond the cerebellar system [16]. ADLL was also found to correct lysosomal pathology in fibroblasts of Tangier disease patients [17]. Tangier disease is due to mutations in the ATP-binding cassette transporter subfamily A number 1 (ABCA1), and has convergent cellular pathology with NPC [17], suggesting that this modified leucine amino acid can display benefit as a disease modifier in diseases with different aetiologies.…”

Section: Introductionmentioning

confidence: 97%

“…ADLL was also found to correct lysosomal pathology in fibroblasts of Tangier disease patients [17]. Tangier disease is due to mutations in the ATP-binding cassette transporter subfamily A number 1 (ABCA1), and has convergent cellular pathology with NPC [17], suggesting that this modified leucine amino acid can display benefit as a disease modifier in diseases with different aetiologies. Recently, acetyl-L-leucine has been identified as the pharmacologically active enantiomer [18,19].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Kaya

Smith

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

Sandhoff disease is a rare neurodegenerative lysosomal storage disease associated with the storage of GM2 ganglioside in late endosomes/lysosomes. Here, we explored the efficacy of acetyl-DL-leucine (ADLL), which has been shown to improve ataxia in observational studies in patients with Niemann-Pick Type C1 and other cerebellar ataxias. We treated a mouse model of Sandhoff disease (Hexb -/-) (0.1 g/kg/day) from 3 weeks of age with this orally available drug. ADLL produced a modest but significant increase in life span, accompanied by improved motor function and reduced glycosphingolipid (GSL) storage in the forebrain and cerebellum, in particular GA2. ADLL was also found to normalize altered glucose and glutamate metabolism, as well as increasing autophagy and the reactive oxygen species (ROS) scavenger, superoxide dismutase (SOD1). Our findings provide new insights into metabolic abnormalities in Sandhoff disease, which could be targeted with new therapeutic approaches, including ADLL.

show abstract

“…Miglustat has been shown to delay neurological symptoms and prolong lifespans [7][8][9] in NPC animal models, suppress neurological deficits, such as gait disorder, dysphagia, cataplexy, and dystonia, and improve ambulation and swallowing abilities in patients with NPC [10][11][12][13][14]. Recently, Colaco et al [15] reported that miglustat appears to have a therapeutic potential against Tangier disease, a metabolic disease caused by a defect in ATP-binding cassette transporter 1, which can be misdiagnosed as NPC.…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

Hoque

Kondo

Sakata

et al. 2020

IJMS

View full text Add to dashboard Cite

Niemann–Pick disease type C (NPC) is an autosomal recessive disorder characterized by abnormal accumulation of free cholesterol and sphingolipids in lysosomes. The iminosugar miglustat, which inhibits hexosylceramide synthesis, is used for NPC treatment, and 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), a cyclic oligosaccharide derivative, is being developed to treat NPC. Moreover, therapeutic potential of 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD) was shown in NPC models, although its mechanism of action remains unclear. Here, we investigated the effects of HP-β-CD, HP-γ-CD, and their homolog 2-hydroxypropyl-α-cyclodextrin (HP-α-CD) on lipid accumulation in Npc1-null Chinese hamster ovary (CHO) cells compared with those of miglustat. HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced intracellular free cholesterol levels and normalized the lysosome changes in Npc1-null cells but not in wild-type CHO cells. In contrast, miglustat did not normalize intracellular free cholesterol accumulation or lysosome changes in Npc1-null cells. However, miglustat decreased the levels of hexosylceramide and tended to increase those of sphingomyelins in line with its action as a glucosylceramide synthase inhibitor in both Npc1-null and wild-type CHO cells. Interestingly, HP-β-CD and HP-γ-CD, unlike HP-α-CD, reduced sphingomyelins in Npc1-null, but not wild-type, cells. In conclusion, HP-β-CD and HP-γ-CD reduce the accumulation of sphingolipids, mainly sphingomyelins, and free cholesterol as well as lysosome changes in Npc1-null, but not in wild-type, CHO cells.

show abstract

Mechanistic convergence and shared therapeutic targets in Niemann‐Pick disease

Abstract: Niemann-Pick disease type C (

Cited by 13 publications

References 43 publications

Defective platelet function in Niemann‐Pick disease type C1

Defective platelet function in Niemann‐Pick disease type C1

Beneficial Effects of Acetyl-DL-Leucine (ADLL) in a Mouse Model of Sandhoff Disease

Differential Effects of 2-Hydroxypropyl-Cyclodextrins on Lipid Accumulation in Npc1-Null Cells

Contact Info

Product

Resources

About