Article
Biochemistry & Molecular Biology
Kristina Dominko, Ana Rastija, Sandra Sobocanec, Lea Vidatic, Sarah Meglaj, Andrea Lovincic Babic, Birgit Hutter-Paier, Alessio-Vittorio Colombo, Stefan F. Lichtenthaler, Sabina Tahirovic, Silva Hecimovic
Summary: In Niemann-Pick type C disease (NPC), impaired retromer function is observed, potentially related to the pathogenesis of the disease, with cholesterol accumulation being a mechanistic factor. This defect is already present in the early stages of NPC disease, suggesting that rescuing retromer impairment could be a novel therapeutic approach against NPC.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Ting-Ting Chu, Xintao Tu, Kun Yang, Jianjun Wu, Joyce J. Repa, Nan Yan
Summary: This study identifies a cGAS- and cGAMP-independent mode of STING activation that affects neuropathology and provides a therapeutic target for the treatment of Niemann-Pick disease type C.
Article
Chemistry, Medicinal
Renshuai Zhang, Wenjing Liu, Jun Zeng, Jingsen Meng, Hongfei Jiang, Jie Wang, Dongming Xing
Summary: Cholesterol is a critical component of cell membranes, but elevated serum cholesterol levels are a major risk factor for heart disease. Understanding and developing NPC1L1 inhibitors, which can decrease cholesterol absorption, is an important research direction that presents both challenges and exciting therapeutic opportunities.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Sandra Torres, Estel Solsona-Vilarrasa, Susana Nunez, Nuria Matias, Naroa Insausti-Urkia, Fernanda Castro, Mireia Casasempere, Gemma Fabrias, Josefina Casas, Carlos Enrich, Jose C. Fernandez-Checa, Carmen Garcia-Ruiz
Summary: NPC disease is characterized by the accumulation of cholesterol and glycosphingolipids in lysosomes, as well as an increase of mitochondrial cholesterol levels, leading to impaired mitochondrial function and GSH depletion. The study reveals a functional relationship between ACDase and STARD1 in NPC disease, and shows a cholesterol-dependent inverse relationship between the two proteins. Targeting the accumulation of cholesterol in mitochondria through manipulating ACDase and STARD1 provides a novel approach to treating NPC disease.
Article
Biochemistry & Molecular Biology
Ana C. Carreira, Sarka Pokorna, Ana E. Ventura, Mathew W. Walker, Anthony H. Futerman, Emyr Lloyd-Evans, Rodrigo F. M. de Almeida, Liana C. Silva
Summary: Niemann-Pick disease type C (NPC) is a complex and rare pathology primarily linked to mutations in the NPC1 gene. The abnormal accumulation of sphingosine may play a key role in the development of NPC, impacting membrane fluidity. Research shows that the addition of sphingosine can alter membrane fluidity, providing new insights into the pathophysiology of NPC.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2021)
Article
Biochemistry & Molecular Biology
Graciela Arguello, Elisa Balboa, Pablo J. Tapia, Juan Castro, Maria Jose Yanez, Pamela Mattar, Rodrigo Pulgar, Silvana Zanlungo
Summary: Niemann-Pick type C disease (NPCD) is a lysosomal storage disease characterized by abnormal cholesterol accumulation in lysosomes. Activation of transcription factor EB (TFEB) by genistein can correct pathological phenotypes in NPC models by improving lysosomal function and autophagic flux. These results suggest that genistein-mediated TFEB activation could be a potential therapeutic agent for treating NPCD and other LSDs with neurological compromise.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Developmental Biology
Wei-Chia Tseng, Ana J. Johnson Escauriza, Chon-Hwa Tsai-Morris, Benjamin Feldman, Ryan K. Dale, Christopher A. Wassif, Forbes D. Porter
Summary: NPC is a rare, fatal neurodegenerative lysosomal disease caused by mutations in NPC1 or NPC2, resulting in the accumulation of cholesterol and other lipids in the lysosome and reduction in cellular cholesterol bioavailability.
Article
Oncology
Yusei Yamada, Madoka Fukaura-Nishizawa, Asami Nishiyama, Akira Ishii, Tatsuya Kawata, Aina Shirakawa, Mayuko Tanaka, Yuki Kondo, Toru Takeo, Naomi Nakagata, Toru Miwa, Hiroki Takeda, Yorihisa Orita, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Takahiro Seki, Yuki Kurauchi, Hiroshi Katsuki, Katsumi Higaki, Kentaro Minami, Naoki Yoshikawa, Ryuji Ikeda, Muneaki Matsuo, Tetsumi Irie, Yoichi Ishitsuka
Summary: This study investigates the relationship between the formation of cyclodextrin (CD) and unesterified cholesterol (UC) complexes and their therapeutic effectiveness. The findings suggest that the solubility and molecular mechanisms of CD influence the formation and complexation capability of these complexes. The ability of CD derivatives to form 1:1 and 2:1 complexes is correlated with their therapeutic efficacy and toxicity, respectively. These findings highlight the importance of optimizing the molecular structure of CDs to overcome current treatment dilemmas.
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Article
Oncology
Yusei Yamada, Madoka Fukaura-Nishizawa, Asami Nishiyama, Akira Ishii, Tatsuya Kawata, Aina Shirakawa, Mayuko Tanaka, Yuki Kondo, Toru Takeo, Naomi Nakagata, Toru Miwa, Hiroki Takeda, Yorihisa Orita, Keiichi Motoyama, Taishi Higashi, Hidetoshi Arima, Takahiro Seki, Yuki Kurauchi, Hiroshi Katsuki, Katsumi Higaki, Kentaro Minami, Naoki Yoshikawa, Ryuji Ikeda, Muneaki Matsuo, Tetsumi Irie, Yoichi Ishitsuka
Summary: This study found that cyclodextrins can be used to treat Niemann-Pick disease type C (NPC), but concerns about ototoxicity exist. By optimizing the molecular structure of cyclodextrins, this study suggests a way to overcome this dilemma.
CLINICAL AND TRANSLATIONAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Jun Zeng, Wenjing Liu, Bing Liang, Lingyu Shi, Shanbo Yang, Jingsen Meng, Jing Chang, Xiaokun Hu, Renshuai Zhang, Dongming Xing
Summary: This study found that isoliquiritigenin (ISL) can lower cholesterol levels by downregulating NPC1L1 expression and competitively inhibiting cellular cholesterol uptake. This provides a theoretical basis for further investigating the molecular mechanisms of its cholesterol-lowering effect and inspires new drug research for cholesterol-lowering purposes through NPC1L1 inhibition.
Article
Chemistry, Multidisciplinary
Insung Kang, Je Min Yoo, Donghoon Kim, Juhee Kim, Myung Keun Cho, Seung-Eun Lee, Dong Jin Kim, Byung-Chul Lee, Jin Young Lee, Jae-Jun Kim, Nari Shin, Soon Won Choi, Young-Ho Lee, Han Seok Ko, Seokmin Shin, Byung Hee Hong, Kyung-Sun Kang
Summary: Graphene quantum dots (GQDs) show promise as a potential therapeutic agent for Niemann-Pick disease type C (NPC) by reducing cholesterol aggregation in lysosomes, promoting autophagy, and inhibiting Purkinje cell loss in the cerebellum. Their ability to alleviate impaired functions in NPC highlights the potential of GQDs for treating NPC and related disorders.
Review
Chemistry, Medicinal
Marcos Morales-Tenorio, Tiziana Ginex, Miguel Angel Cuesta-Geijo, Nuria E. Campillo, Cesar Munoz-Fontela, Covadonga Alonso, Rafael Delgado, Carmen Gil
Summary: The Niemann-Pick C1 (NPC1) receptor plays a crucial role in regulating intracellular cholesterol trafficking and facilitating the entry of Ebola virus into host cells. Disruption of the NPC1/EBOV-GP interaction could be a promising strategy for developing drugs to inhibit viral entry and infection, although further research is needed to understand the molecular and structural details of this interaction.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Shiqian Han, Qijun Wang, Yongfeng Song, Mao Pang, Chunguang Ren, Jing Wang, Dongwei Guan, Wei Xu, Fangyong Li, Fengchao Wang, Xinyuan Zhou, Carlos Fernandez-Hernando, Huiwen Zhang, Dianqing Wu, Zhijia Ye
Summary: Niemann-Pick disease type C (NP-C) is a genetic lysosomal disorder with limited therapeutic options. This study demonstrates that lithium treatment improves phenotypes and extends survival in NP-C mouse models by suppressing STING activation, SREBP2 processing, and target gene expression. Lithium impedes STING/SREBP2 transport, providing a mechanistic explanation for its effects. This reveals a potential therapeutic option for NP-C patients and a strategy to reduce active STING/SREBP2 pathway.
Review
Biochemistry & Molecular Biology
Antonietta Bernardo, Chiara De Nuccio, Sergio Visentin, Alberto Martire, Luisa Minghetti, Patrizia Popoli, Antonella Ferrante
Summary: Niemann-Pick type C (NPC) disease is a neurovisceral disorder that mainly affects the liver and brain, caused by mutations in genes coding for proteins involved in cholesterol transport. NPC leads to the accumulation of unesterified cholesterol in lysosomes, affecting mitochondrial function and leading to neurodegeneration and myelin defects in the brain. Emerging pharmacological strategies targeting A(2A) adenosine receptor stimulation show promise for NPC therapy.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Nina H. Pipalia, Syed Z. Saad, Kanagaraj Subramanian, Abigail Cross, Aisha Al-Motawa, Kunal Garg, Brian S. J. Blagg, Len Neckers, Paul Helquist, Olaf Wiest, Daniel S. Ory, Frederick R. Maxfield
Summary: Inhibition of HSP90 clears cholesterol from LE/Ly in NPC1(I1061T) fibroblasts and enhances delivery of mutant NPC1(I1061T) protein. Additionally, HSP90 inhibition increases HSP70 expression, and overexpression of HSP70 reduces cholesterol storage in NPC1(I1061T) fibroblasts. This suggests that HSP90 inhibitors may improve NPC1 protein folding and relieve cholesterol accumulation in NPC1 mutant fibroblasts by increasing other chaperones.
JOURNAL OF LIPID RESEARCH
(2021)