Biophysical impact of sphingosine and other abnormal lipid accumulation in Niemann-Pick disease type C cell models

Carreira, Ana C.; Pokorná, Šárka; Ventura, Ana E.; Walker, Mathew; Futerman, Anthony H.; Lloyd-Evans, Emyr; Almeida, Rodrigo F.M. de; Silva, Liana C.

doi:10.1016/j.bbalip.2021.158944

Cited by 2 publications

(3 citation statements)

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“…The accumulation of sphingosine has been observed in mouse models as well as in NPC cell lines [32,84]. Sphingosine is a sphingolipid synthesized from ceramide and is considered an activator of apoptosis due to its properties of penetrating the lysosomal membrane and promoting the release of lysosomal hydrolases that damage the mitochondrial membrane.…”

Section: Alterations In Lysosomal Glycocalyxmentioning

confidence: 99%

“…In contrast, phosphorylated sphingosine (S-1P) has been identified as a molecule that inhibits apoptosis [85,86]. In several cellular models of NPC, it has been observed that sphingosine accumulation causes changes in the plasma membrane and the fluidity of the lysosomal membranes [32]. Such accumulation of sphingosine in NPC may be due to the observed reduction in sphingosine kinase 1 (SphK1), which is one of the enzymes that phosphorylates sphingosine [87].…”

Section: Alterations In Lysosomal Glycocalyxmentioning

confidence: 99%

“…For instance, the increased affinity of dynein for cholesterol-rich membranes keeps endolysosomes away from the periphery, preventing their recycling [28][29][30][31]. Moreover, sphingosine accumulation results in changes in the permeability of the lysosomal glycocalyx, leading to the release of proteases [32]. Additionally, the reduction in lysosomal calcium release due to sphingomyelin accumulation causes dysfunction in the fusion of lysosomes with early endosomes and autophagosomes, thereby impacting the degradation of components [33,34].…”

Section: Introductionmentioning

confidence: 99%

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Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease

Servín Muñoz,

Ortuño-Sahagún,

Griñán-Ferré

et al. 2024

IJMS

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Niemann–Pick Type C (NPC) represents an autosomal recessive disorder with an incidence rate of 1 in 150,000 live births, classified within lysosomal storage diseases (LSDs). The abnormal accumulation of unesterified cholesterol characterizes the pathophysiology of NPC. This phenomenon is not unique to NPC, as analogous accumulations have also been observed in Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative disorders. Interestingly, disturbances in the folding of the mutant protein NPC1 I1061T are accompanied by the aggregation of proteins such as hyperphosphorylated tau, α-synuclein, TDP-43, and β-amyloid peptide. These accumulations suggest potential disruptions in proteostasis, a regulatory process encompassing four principal mechanisms: synthesis, folding, maintenance of folding, and protein degradation. The dysregulation of these processes leads to excessive accumulation of abnormal proteins that impair cell function and trigger cytotoxicity. This comprehensive review delineates reported alterations across proteostasis mechanisms in NPC, encompassing changes in processes from synthesis to degradation. Additionally, it discusses therapeutic interventions targeting pharmacological facets of proteostasis in NPC. Noteworthy among these interventions is valproic acid, a histone deacetylase inhibitor (HDACi) that modulates acetylation during NPC1 synthesis. In addition, various therapeutic options addressing protein folding modulation, such as abiraterone acetate, DHBP, calnexin, and arimoclomol, are examined. Additionally, treatments impeding NPC1 degradation, exemplified by bortezomib and MG132, are explored as potential strategies. This review consolidates current knowledge on proteostasis dysregulation in NPC and underscores the therapeutic landscape targeting diverse facets of this intricate process.

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Section: Alterations In Lysosomal Glycocalyxmentioning

confidence: 99%