Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease
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...
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| Format: | Article |
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MDPI AG
2024-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/7/3806 |
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| author | Iris Valeria Servín Muñoz Daniel Ortuño-Sahagún Christian Griñán-Ferré Mercè Pallàs Celia González-Castillo |
| author_facet | Iris Valeria Servín Muñoz Daniel Ortuño-Sahagún Christian Griñán-Ferré Mercè Pallàs Celia González-Castillo |
| author_sort | Iris Valeria Servín Muñoz |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-24T10:43:17Z |
| format | Article |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-04-24T10:43:17Z |
| publishDate | 2024-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-578ac6082aa34d10a636a3ca13bff91c2024-04-12T13:19:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-03-01257380610.3390/ijms25073806Alterations in Proteostasis Mechanisms in Niemann–Pick Type C DiseaseIris Valeria Servín Muñoz0Daniel Ortuño-Sahagún1Christian Griñán-Ferré2Mercè Pallàs3Celia González-Castillo4Laboratorio de Neuroinmunobiología Molecular, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, MexicoLaboratorio de Neuroinmunobiología Molecular, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, MexicoPharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, Universitat de Barcelona, 08028 Barcelona, SpainPharmacology Section, Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, Institute of Neuroscience, Universitat de Barcelona, 08028 Barcelona, SpainTecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan 45201, MexicoNiemann–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.https://www.mdpi.com/1422-0067/25/7/3806lysosomelysosomal storage diseases (LSDs)cholesterolprotein degradationprotein folding |
| spellingShingle | Iris Valeria Servín Muñoz Daniel Ortuño-Sahagún Christian Griñán-Ferré Mercè Pallàs Celia González-Castillo Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease International Journal of Molecular Sciences lysosome lysosomal storage diseases (LSDs) cholesterol protein degradation protein folding |
| title | Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease |
| title_full | Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease |
| title_fullStr | Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease |
| title_full_unstemmed | Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease |
| title_short | Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease |
| title_sort | alterations in proteostasis mechanisms in niemann pick type c disease |
| topic | lysosome lysosomal storage diseases (LSDs) cholesterol protein degradation protein folding |
| url | https://www.mdpi.com/1422-0067/25/7/3806 |
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