Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease
Abstract
:1. Introduction
1.1. N-Glycosylation, Implication in NPC1 Function
1.2. ERAD Pathway and Chaperone Folding
1.3. Folding by Heat Shock Proteins
2. Autophagy in NPC
Alterations in ER-Phagy
3. Lysosomal Degradation Pathway
3.1. Alterations in Endocytosis Due to Cholesterol Accumulation in NPC
3.2. Alterations in Lysosomal Glycocalyx
3.3. Dysregulation of Calcium Concentration
4. Ubiquitin–Proteosome Pathway
5. Therapies Based on the Improvement of Proteostasis
6. Conclusions and Perspectives
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Mechanism of Proteostasis in Which It Is Involved | Therapy or Therapeutic Target | Mechanism of Action | Effects | Considerations | Ref. |
---|---|---|---|---|---|
Synthesis | Valproic acid (VPA) and chloroquine | VPA reduces HDAC7 expression and increases NPC1 acetylation, and chloroquine neutralizes lysosomal hyperacidity. | Promotes folding and transport of NPC1-I1061T to LE/Ly, reduces cholesterol accumulation in NPC1-I1061T fibroblasts. | Valproic acid can cross the blood–brain barrier and can be administered orally. Treatment with VPA can alter the pH of the lysosome, so that combined treatment with chloroquine stabilizes the pH and has better effects. | [108] |
Glycosylation | Itraconazole | Inhibits protein glycosylation; highly glycosylated proteins coat the lysosomal inner membrane, so the inhibition of glycosylation may cause increased permeability of the lysosomal glycocalyx, which increases the release of cholesterol into the lysosomes. | At high concentrations (10 μM), it significantly reduces cholesterol accumulation. | It has a slight effect on reducing cholesterol accumulation at low concentrations, possibly because it also inhibits the glycosylation of the NPC1 protein, which affects its function. | [39] |
Folding | Abiraterone acetate | Interacts with NTD of NPC1 to mediate its folding. | Reduction in cholesterol concentration; upregulation and co-localization in lysosomes of NPC1 resistant to EndoH in three different mutations NPC1 E612D/P543Rfs*, I1061T, NPC1 Y394H/Y394H; these results show it as an effective treatment. | It is a drug approved by the FDA and the EMA for prostate cancer; its active metabolite is abiraterone; in animal models, it has been observed that it crosses the blood–brain barrier. | [21] |
DHBP | Inhibits ryanodine receptors and increases calcium levels in the ER; promotes the folding of NPC1 by calcium-dependent chaperones. | Increases levels of EndoH-resistant NPC1 I1061T, promotes the trafficking of NPC1 I1061T to lysosomes, and regulates the accumulation of cholesterol and sphingolipids. | With this treatment, it was observed that only the trafficking of a small fraction of NPC1 I1061T improved, but the reduction in cholesterol was significant. | [22] | |
Calnexine | Mediates NPC1 I1061T folding. | Enhances trafficking of NPC1 I1061T to lysosomes and regulates the accumulation of cholesterol and sphingolipids. | Despite only increasing the transport of a low level of NPC1 I1061T NPC1, the reduction in cholesterol was significant. | [22] | |
Arimoclomol | Co-induces heat shock proteins by stabilizing their interaction between heat shock factor (HSF-1) and HSES, which mediate the transcription of HSPs. | The treatment had significant effects on reducing the progression of NPC; increased HSP70 expression and reduced lipid accumulation. | Safety studies in patients with CPN show that the most common adverse event was vomiting (23.5%), and six of the patients presented increased serum creatinine. | [24,25] | |
Recombinant human heat shock protein 70 (rhHSP70) | Amplification of HSP70 and therefore enhancement of sphingolipid-degrading enzymes. | Normalizes the oligodendrocyte population and rescues it from cerebellar atrophy; improved myelination in cerebellum; reduced GSL accumulation and improved NPC phenotype in a murine model. | In the study, treatment with rhHSP70 showed an improvement in myelination in the cerebellum; however, it is not known if the treatment is effective for increasing Npc1 levels and transport or if it is able to reduce cholesterol accumulation. | [46] | |
Recombinant HSP70 | Enhance NPC1 folding and enhancement of sphingolipid-degrading enzymes. | Reduced GM1 ganglioside accumulation; improved the motor phenotype in a murine model. | This treatment is not effective in knockout models, only in nonsense mutations. | [24] | |
JG98 inhibitor | Disrupts the interaction between Hsp70 and BAG-1 and -3, which mediate the degradation of Hsp70 by the ubiquitin–proteasome system or the lysosomal autophagic pathway. | Correction in the trafficking of 58 NPC1 variants and reduction in the activation of SREBP-2, a transcription factor that regulates the expression of genes that participate in the synthesis of fatty acids. | This treatment showed significant responses even in variants with null or reduced activity of NPC1 transport and function; however, one of the disadvantages is that it is a fluorescent molecule, so that monitoring of cholesterol accumulation by filipin staining is not feasible. | [27,109] | |
AUY922 | Inhibition of HSP90, which when inactive mediates the release of HSF1 factor and promotes the expression of HSPs. | Overexpression of HSP70 and HSP40, increased transport of NPC1 from ER to LE/Ly and decreased cholesterol concentration. | The treatment with this drug for NPC has only been performed in vitro, but in the treatment of solid tumors it has been observed that the main adverse event is fatigue and decreased appetite. | [26,110] | |
Overexpression of hspb1 | Phosphorylated Hspb1 provides a neuroprotective effect by having anti-apoptotic functions. | In mice, there was delayed motor impairment and decreased Purkinje cell loss. In cells, promotes neuronal survival. | Hspb1 as a therapeutic target was only proven to be effective in reducing Purkinje cell loss in a murine model, but it was not evaluated whether there was a reduction in the accumulation of cholesterol or other fatty acids, so its effectiveness in this aspect cannot be determined. | [49] | |
Lysosomal pathway | Overexpression of TRPML1 receptor | Increasing its expression improves lysosomal calcium release, which is favorable for the fusion of LE and Ly and Ly with autophagosomes. | Enhances lysosomal trafficking and rescues it from cholesterol storage. | This treatment offers another approach that does not act directly on NPC1 or NPC2 proteins but improves lysosomal trafficking; also decreases cholesterol concentrations. | [96] |
Degradation | Bortezomib treatment | Inhibits the 26s proteasome by inactivation of the chymotrypsin-like site in the proteolytic nucleus. | Partially increases NPC1 levels and reduces cholesterol content. | This treatment is not completely effective because it does not increase the co-localization of NPC1 to lysosomes despite showing a reduction in cholesterol accumulation. | [107,111] |
MG132 | Inhibits the 26s proteasome | Increased NPC1 protein expression and co-localization within the endolysosomal compartment, reduction of GM1 accumulation, reduced cholesterol concentrations. | According to the study, it is not a safe treatment; at doses higher than 500 nM, there is reduction in cell viability; this treatment was shown to be effective in increasing NPC1 protein levels in fibroblast cell lines of six mutant variants. | [106] |
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Servín Muñoz, I.V.; Ortuño-Sahagún, D.; Griñán-Ferré, C.; Pallàs, M.; González-Castillo, C. Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease. Int. J. Mol. Sci. 2024, 25, 3806. https://doi.org/10.3390/ijms25073806
Servín Muñoz IV, Ortuño-Sahagún D, Griñán-Ferré C, Pallàs M, González-Castillo C. Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease. International Journal of Molecular Sciences. 2024; 25(7):3806. https://doi.org/10.3390/ijms25073806
Chicago/Turabian StyleServín Muñoz, Iris Valeria, Daniel Ortuño-Sahagún, Christian Griñán-Ferré, Mercè Pallàs, and Celia González-Castillo. 2024. "Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease" International Journal of Molecular Sciences 25, no. 7: 3806. https://doi.org/10.3390/ijms25073806