Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C disease but is not sufficient to halt neurodegeneration
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 22:166993. doi: 10.1016/j.bbadis.2023.166993. Online ahead of print.ABSTRACTCholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann-Pick type C (NPC) disease, a rare and fatal ne...
Source: Biochimica et Biophysica Acta - December 24, 2023 Category: Biochemistry Authors: Maria Jo ão Nunes Andreia Neves Carvalho Joana Reis Daniela Costa Miguel Moutinho Joana Mateus Rita Mendes de Almeida Sara Brito Daniela Risso Sofia Nunes Margarida Castro-Caldas Maria Jo ão Gama Cec ília M P Rodrigues Sara Xapelli Maria Jos é Diógen Source Type: research
Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C disease but is not sufficient to halt neurodegeneration
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 22:166993. doi: 10.1016/j.bbadis.2023.166993. Online ahead of print.ABSTRACTCholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann-Pick type C (NPC) disease, a rare and fatal ne...
Source: Biochimica et Biophysica Acta - December 24, 2023 Category: Biochemistry Authors: Maria Jo ão Nunes Andreia Neves Carvalho Joana Reis Daniela Costa Miguel Moutinho Joana Mateus Rita Mendes de Almeida Sara Brito Daniela Risso Sofia Nunes Margarida Castro-Caldas Maria Jo ão Gama Cec ília M P Rodrigues Sara Xapelli Maria Jos é Diógen Source Type: research
Cholesterol redistribution triggered by CYP46A1 gene therapy improves major hallmarks of Niemann-Pick type C disease but is not sufficient to halt neurodegeneration
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 22:166993. doi: 10.1016/j.bbadis.2023.166993. Online ahead of print.ABSTRACTCholesterol 24-hydroxylase (CYP46A1) is an exclusively neuronal cytochrome P450 enzyme responsible for converting cholesterol into 24S-hydroxycholesterol, which serves as the primary pathway for eliminating cholesterol in the brain. We and others have shown that increased activity of CYP46A1 leads to reduced levels of cholesterol and has a positive effect on cognition. Therefore, we hypothesized that CYP46A1 could be a potential therapeutic target in Niemann-Pick type C (NPC) disease, a rare and fatal ne...
Source: Biochimica et Biophysica Acta - December 24, 2023 Category: Biochemistry Authors: Maria Jo ão Nunes Andreia Neves Carvalho Joana Reis Daniela Costa Miguel Moutinho Joana Mateus Rita Mendes de Almeida Sara Brito Daniela Risso Sofia Nunes Margarida Castro-Caldas Maria Jo ão Gama Cec ília M P Rodrigues Sara Xapelli Maria Jos é Diógen Source Type: research
An overview of the role of Niemann-pick C1 (NPC1) in viral infections and inhibition of viral infections through NPC1 inhibitor
Viruses communicate with their hosts through interactions with proteins, lipids, and carbohydrate moieties on the plasma membrane (PM), often resulting in viral absorption via receptor-mediated endocytosis. Ma... (Source: Cell Communication and Signaling)
Source: Cell Communication and Signaling - December 14, 2023 Category: Molecular Biology Authors: Irfan Ahmad, Seyede Narges Fatemi, Mohammad Ghaheri, Ali Rezvani, Dorsa Azizi Khezri, Mohammad Natami, Saman Yasamineh, Omid Gholizadeh and Zahra Bahmanyar Tags: Review Source Type: research
Npc1 gene mutation abnormally activates the classical Wnt signalling pathway in mouse kidneys and promotes renal fibrosis
Anim Genet. 2023 Dec 12. doi: 10.1111/age.13381. Online ahead of print.ABSTRACTNiemann-Pick disease type C1 (NPC1) is a lysosomal lipid storage disease caused by NPC1 gene mutation. Our previous study found that, compared with wild-type (Npc1+/+ ) mice, the renal volume and weight of Npc1 gene mutant (Npc1-/- ) mice were significantly reduced. We speculate that Npc1 gene mutations may affect the basic structure of the kidneys of Npc1-/- mice, and thus affect their function. Therefore, we randomly selected postnatal Day 28 (P28) and P56 Npc1+/+ and Npc1-/- mice, and observed the renal structure and pathological changes by h...
Source: Animal Genetics - December 13, 2023 Category: Genetics & Stem Cells Authors: Lihong Guan Zisen Jia Keli Xu Minlin Yang Xiaoying Li Liang Qiao Yanli Liu Juntang Lin Source Type: research
Npc1 gene mutation abnormally activates the classical Wnt signalling pathway in mouse kidneys and promotes renal fibrosis
Anim Genet. 2023 Dec 12. doi: 10.1111/age.13381. Online ahead of print.ABSTRACTNiemann-Pick disease type C1 (NPC1) is a lysosomal lipid storage disease caused by NPC1 gene mutation. Our previous study found that, compared with wild-type (Npc1+/+ ) mice, the renal volume and weight of Npc1 gene mutant (Npc1-/- ) mice were significantly reduced. We speculate that Npc1 gene mutations may affect the basic structure of the kidneys of Npc1-/- mice, and thus affect their function. Therefore, we randomly selected postnatal Day 28 (P28) and P56 Npc1+/+ and Npc1-/- mice, and observed the renal structure and pathological changes by h...
Source: Animal Genetics - December 13, 2023 Category: Genetics & Stem Cells Authors: Lihong Guan Zisen Jia Keli Xu Minlin Yang Xiaoying Li Liang Qiao Yanli Liu Juntang Lin Source Type: research
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 5:166980. doi: 10.1016/j.bbadis.2023.166980. Online ahead of print.ABSTRACTDisruption of brain cholesterol homeostasis has been implicated in neurodegeneration. Nevertheless, the role of cholesterol in Parkinson's Disease (PD) remains unclear. We have used N2a mouse neuroblastoma cells and primary cultures of mouse neurons and 1-methyl-4-phenylpyridinium (MPP+), a known mitochondrial complex I inhibitor and the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), known to trigger a cascade of events associated with PD neuropathological features. Simultaneousl...
Source: Biochimica et Biophysica Acta - December 7, 2023 Category: Biochemistry Authors: In ês Caria Maria Jo ão Nunes Viviana Ciraci Andreia Neves Carvalho Catarina Ranito Susana G Santos Maria Jo ão Gama Margarida Castro-Caldas Cec ília M P Rodrigues Jorge L Ruas Elsa Rodrigues Source Type: research
NPC1-like phenotype, with intracellular cholesterol accumulation and altered mTORC1 signaling in models of Parkinson's disease
Biochim Biophys Acta Mol Basis Dis. 2023 Dec 5:166980. doi: 10.1016/j.bbadis.2023.166980. Online ahead of print.ABSTRACTDisruption of brain cholesterol homeostasis has been implicated in neurodegeneration. Nevertheless, the role of cholesterol in Parkinson's Disease (PD) remains unclear. We have used N2a mouse neuroblastoma cells and primary cultures of mouse neurons and 1-methyl-4-phenylpyridinium (MPP+), a known mitochondrial complex I inhibitor and the toxic metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), known to trigger a cascade of events associated with PD neuropathological features. Simultaneousl...
Source: Biochimica et Biophysica Acta - December 7, 2023 Category: Biochemistry Authors: In ês Caria Maria Jo ão Nunes Viviana Ciraci Andreia Neves Carvalho Catarina Ranito Susana G Santos Maria Jo ão Gama Margarida Castro-Caldas Cec ília M P Rodrigues Jorge L Ruas Elsa Rodrigues Source Type: research
Comparative Hippocampal Proteome and Phosphoproteome in a Niemann-Pick, Type C1 Mouse Model Reveal Insights into Disease Mechanisms
J Proteome Res. 2023 Nov 24. doi: 10.1021/acs.jproteome.3c00375. Online ahead of print.ABSTRACTNiemann-Pick disease, type C (NPC) is a neurodegenerative, lysosomal storage disorder in individuals carrying two mutated copies of either the NPC1 or NPC2 gene. Consequently, impaired cholesterol recycling and an array of downstream events occur. Interestingly, in NPC, the hippocampus displays lysosomal lipid storage but does not succumb to progressive neurodegeneration as significantly as other brain regions. Since defining the neurodegeneration mechanisms in this disease is still an active area of research, we use mass spectro...
Source: Cell Research - November 24, 2023 Category: Cytology Authors: Thu T A Nguyen Varshasnata Mohanty Ying Yan Kevin R Francis Stephanie M Cologna Source Type: research
Ocular manifestation of an adult Niemann-Pick disease type B
Orv Hetil. 2023 Nov 19;164(46):1838-1844. doi: 10.1556/650.2023.32927. Print 2023 Nov 19.ABSTRACTNiemann-Pick disease is a rare, autosomal recessive inherited lysosomal storage disorder. The pathophysiological background for this condition is the deficiency or reduced function of the enzyme sphingomyelinase, as well as a deficiency in the intracellular cholesterol transporter protein. Due to the breakdown defect, sphingomyelin and cholesterol accumulate in the lysosomes of cells. The disease is divided into 5 subtypes (A, A/B, B, C, D). The authors present the case of a 24-year-old young man diagnosed with Niemann-Pick dis...
Source: Orvosi Hetilap - November 19, 2023 Category: General Medicine Authors: Orsolya Angeli Zolt án Nagy Mikl ós Schneider Source Type: research
Ocular manifestation of an adult Niemann-Pick disease type B
Orv Hetil. 2023 Nov 19;164(46):1838-1844. doi: 10.1556/650.2023.32927. Print 2023 Nov 19.ABSTRACTNiemann-Pick disease is a rare, autosomal recessive inherited lysosomal storage disorder. The pathophysiological background for this condition is the deficiency or reduced function of the enzyme sphingomyelinase, as well as a deficiency in the intracellular cholesterol transporter protein. Due to the breakdown defect, sphingomyelin and cholesterol accumulate in the lysosomes of cells. The disease is divided into 5 subtypes (A, A/B, B, C, D). The authors present the case of a 24-year-old young man diagnosed with Niemann-Pick dis...
Source: Orvosi Hetilap - November 19, 2023 Category: General Medicine Authors: Orsolya Angeli Zolt án Nagy Mikl ós Schneider Source Type: research
Hydroxypropyl- β-cyclodextrin inhibits the development of triple negative breast cancer by enhancing antitumor immunity
Int Immunopharmacol. 2023 Nov 6;125(Pt A):111168. doi: 10.1016/j.intimp.2023.111168. Online ahead of print.ABSTRACTTriple negative breast cancer (TNBC) is regarded as one of the most aggressive forms of breast cancer. Hydroxypropyl-β-cyclodextrin (HP-β-CD) has been used as a therapeutic agent for Niemann-Pick disease Type C (NPC). However, the exact actions and mechanisms of HP-β-CD on TNBC are not fully understood. To examine the influence of HP-β-CD on the proliferation and migration of TNBC cell lines, particularly 4T1 and MDA-MB-231 cells, a range of assays, including MTT, scratch, cell cycle, and clonal formation ...
Source: International Immunopharmacology - November 8, 2023 Category: Allergy & Immunology Authors: Mengmeng Zhu Qian Zhao Wenwen Zhang Hongmei Xu Baotong Zhang Shuang Zhang Yajun Duan Chenzhong Liao Xiaoxiao Yang Yuanli Chen Source Type: research
Automated quantification of vacuole fusion and lipophagy in < em > Saccharomyces cerevisiae < /em > from fluorescence and cryo-soft X-ray microscopy data using deep learning
Autophagy. 2023 Oct 31:1-21. doi: 10.1080/15548627.2023.2270378. Online ahead of print.ABSTRACTDuring starvation in the yeast Saccharomyces cerevisiae vacuolar vesicles fuse and lipid droplets (LDs) can become internalized into the vacuole in an autophagic process named lipophagy. There is a lack of tools to quantitatively assess starvation-induced vacuole fusion and lipophagy in intact cells with high resolution and throughput. Here, we combine soft X-ray tomography (SXT) with fluorescence microscopy and use a deep-learning computational approach to visualize and quantify these processes in yeast. We focus on yeast homolo...
Source: Autophagy - November 1, 2023 Category: Cytology Authors: Jacob Marcus Egebjerg Maria Szomek Katja Thaysen Alice Dupont Juhl Suzana Kozakijevic Stephan Werner Christoph Pratsch Gerd Schneider Sergey Kapishnikov Axel Ekman Richard R öttger Daniel W üstner Source Type: research
Automated quantification of vacuole fusion and lipophagy in < em > Saccharomyces cerevisiae < /em > from fluorescence and cryo-soft X-ray microscopy data using deep learning
Autophagy. 2023 Oct 31:1-21. doi: 10.1080/15548627.2023.2270378. Online ahead of print.ABSTRACTDuring starvation in the yeast Saccharomyces cerevisiae vacuolar vesicles fuse and lipid droplets (LDs) can become internalized into the vacuole in an autophagic process named lipophagy. There is a lack of tools to quantitatively assess starvation-induced vacuole fusion and lipophagy in intact cells with high resolution and throughput. Here, we combine soft X-ray tomography (SXT) with fluorescence microscopy and use a deep-learning computational approach to visualize and quantify these processes in yeast. We focus on yeast homolo...
Source: Autophagy - November 1, 2023 Category: Cytology Authors: Jacob Marcus Egebjerg Maria Szomek Katja Thaysen Alice Dupont Juhl Suzana Kozakijevic Stephan Werner Christoph Pratsch Gerd Schneider Sergey Kapishnikov Axel Ekman Richard R öttger Daniel W üstner Source Type: research
Association of lipid lowering drugs and the risk of systemic lupus erythematosus: a drug target Mendelian randomization
Conclusion: Evolocumab might provide a protective effect on the risk of SLE in the European population, but statins and ezetimibe might not have the protective effect. Further research is necessary to elucidate the specific mechanisms and potential therapeutic applications of PCSK9 inhibitors (evolocumab) in the context of SLE protection. (Source: Frontiers in Pharmacology)
Source: Frontiers in Pharmacology - October 30, 2023 Category: Drugs & Pharmacology Source Type: research
