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2. Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitro and in vivo
- Author
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Liu, Meng, Zhang, Chao, Gong, Ximing, Zhang, Tian, Lian, Michelle Mulan, Chew, Elaine Guo Yan, Cardilla, Angelysia, Suzuki, Keiichiro, Wang, Huamin, Yuan, Yuan, Li, Yan, Naik, Mihir Yogesh, Wang, Yixuan, Zhou, Bingrui, Soon, Wei Ze, Aizawa, Emi, Li, Pin, Low, Jian Hui, Tandiono, Moses, Montagud, Enrique, Moya–Rull, Daniel, Rodriguez Esteban, Concepcion, Luque, Yosu, Fang, Mingliang, Khor, Chiea Chuen, Montserrat, Nuria, Campistol, Josep M., Izpisua Belmonte, Juan Carlos, Foo, Jia Nee, and Xia, Yun
- Published
- 2024
- Full Text
- View/download PDF
3. Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease
- Author
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Tay, Kai Yi, Wu, Kan Xing, Chioh, Florence Wen Jing, Autio, Matias Ilmari, Pek, Nicole Min Qian, Narmada, Balakrishnan Chakrapani, Tan, Sock-Hwee, Low, Adrian Fatt-Hoe, Lian, Michelle Mulan, Chew, Elaine Guo Yan, Lau, Hwee Hui, Kao, Shih Ling, Teo, Adrian Kee Keong, Foo, Jia Nee, Foo, Roger Sik Yin, Heng, Chew Kiat, Chan, Mark Yan Yee, and Cheung, Christine
- Published
- 2022
- Full Text
- View/download PDF
4. Identification of Genetic Variants in Progressive Supranuclear Palsy in Southeast Asia.
- Author
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Ng, Adeline Su Lyn, Tan, Ai Huey, Tan, Yi Jayne, Lim, Jia Lun, Lian, Michelle Mulan, Dy Closas, Alfand Marl, Ahmad‐Annuar, Azlina, Viswanathan, Shanthi, Chia, Yuen Kang, Foo, Jia Nee, Lim, Weng Khong, Tan, Eng‐King, and Lim, Shen‐Yang
- Abstract
Background: Progressive supranuclear palsy (PSP) is largely a sporadic disease with few reported familial cases. Genome‐wide association studies (GWAS) in sporadic PSP in Caucasian populations have identified MAPT as the most commonly associated genetic risk locus with the strongest effect size. At present there are limited data on genetic factors associated with PSP in Asian populations. Objectives: Our goal was to investigate the genetic factors associated with PSP in Southeast Asian PSP patients. Methods: Next‐generation sequencing (whole‐exome, whole‐genome and targeted sequencing) was performed in two Asian cohorts, comprising 177 PSP patients. Results: We identified 17 pathogenic or likely pathogenic variants in 16 PSP patients (9%), eight of which were novel. The most common relevant genetic variants identified were in MAPT, GBA1, OPTN, SYNJ1, and SQSTM1. Other variants detected were in TBK1, PRNP, and ABCA7—genes that have been implicated in other neurodegenerative diseases. Eighteen patients had a positive family history, of whom two carried pathogenic MAPT variants, and one carried a likely pathogenic GBA1 variant. None of the patients had expanded repeats in C9orf72. Furthermore, we found 16 different variants of uncertain significance in 21 PSP patients in PSEN2, ABCA7, SMPD1, MAPT, ATP13A2, OPTN, SQSTM1, CYLD, and BSN. Conclusions: The genetic findings in our PSP cohorts appear to be somewhat distinct from those in Western populations, and also suggest an overlap of the genetic architecture between PSP and other neurodegenerative diseases. Further functional studies and validation in independent Asian cohorts will be useful for improving our understanding of PSP genetics and guiding genetic screening strategies in these populations. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
- View/download PDF
5. Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
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Le Guen, Yann, Luo, Guo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Yu, Eric, Nicolas, Aude, de Rojasj, Itziar, Leal, Thiago Peixoto, Miyashita, Akinori, Bellenguez, Celine, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier-Boley, Benjamin, Naito, Tatsuhiko, Kucukali, Fahri, Talyansky, Seth D., Yogeshwar, Selina Maria, Sempere, Vicente, Satake, Wataru, Alvarez, Victoria, Arosio, Beatrice, Belloy, Michael E., Benussi, Luisa, Boland, Anne, Borroni, Barbara, Bullido, Maria J., Caffarra, Paolo, Clarimon, Jordi, Daniele, Antonio, Darling, Daniel, Debette, Stephanie, Deleuze, Jean-Francois, Dichgans, Martin, Dufouil, Carole, During, Emmanuel, Duzel, Emrah, Galimberti, Daniela, Garcia-Ribas, Guillermo, Maria Garcia-Alberca, Jose, Garcia-Gonzalez, Pablo, Giedraitis, Vilmantas, Goldhardt, Oliver, Graff, Caroline, Grunblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jung, Yoo Jin, Jurgen, Deckert, Kern, Silke, Kuulasmaa, Teemu, Lee, Kun Ho, Lin, Ling, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonca, Alexandre, Boada, Merce, Mir, Pablo, Moebus, Susanne, Moreno, Fermin, Nacmias, Benedetta, Nicolas, Gael, Niida, Shumpei, Nordestgaard, Borge G., Papenberg, Goran, Papma, Janne, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peters, Oliver, Pijnenburg, Yolande A. L., Pinol-Ripoll, Gerard, Popp, Julius, Porcel, Laura Molina, Jordi Perez-Tur, Raquel Puertaj, Rainero, Innocenzo, Ramakers, Inez, Real, Luis M., Riedel-Heller, Steffi, Rodriguez-Rodriguez, Eloy, Ross, Owen A., Royo, Jose Luis, Rujescu, Dan, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Skoog, Ingmar, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Sanchez-Valle, Raquel, Tan, Eng-King, Tegos, Thomas, Teunissen, Charlotte, Thomassen, Jesper Qvist, Tremolizzo, Lucio, Vyhnalek, Martin, Verhey, Frans, Waern, Margda, Wiltfang, Jens, Zhangc, Jing, Zetterberg, Henrik, Blennow, Kaj, He, Zihuai, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., Andreassen, Ole A., Van Duin, Cornelia, Tsolaki, Magda, Sanchez-Juan, Pascual, Frikke-Schmidt, Ruth, Sleegers, Kristel, Todau, Tatsushi, Zettergren, Anna, Ingelsson, Martin, Okada, Yukinori, Rossi, Giacomina, Hiltunen, Mikko, Gim, Jungsoo, Ozaki, Kouichi, Sims, Rebecca, Foo, Jia Nee, van der Fliere, Wiesje, Ikeuchi, Takeshi, Ramirez, Alfredo, Mata, Ignacio, Ruiz, Agustin, Gan-Or, Ziv, Lambert, Jean-Charles, Greicius, Michael D., Mignot, Emmanuel, Le Guen, Yann, Luo, Guo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Yu, Eric, Nicolas, Aude, de Rojasj, Itziar, Leal, Thiago Peixoto, Miyashita, Akinori, Bellenguez, Celine, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Park, Hyeonseul, Grenier-Boley, Benjamin, Naito, Tatsuhiko, Kucukali, Fahri, Talyansky, Seth D., Yogeshwar, Selina Maria, Sempere, Vicente, Satake, Wataru, Alvarez, Victoria, Arosio, Beatrice, Belloy, Michael E., Benussi, Luisa, Boland, Anne, Borroni, Barbara, Bullido, Maria J., Caffarra, Paolo, Clarimon, Jordi, Daniele, Antonio, Darling, Daniel, Debette, Stephanie, Deleuze, Jean-Francois, Dichgans, Martin, Dufouil, Carole, During, Emmanuel, Duzel, Emrah, Galimberti, Daniela, Garcia-Ribas, Guillermo, Maria Garcia-Alberca, Jose, Garcia-Gonzalez, Pablo, Giedraitis, Vilmantas, Goldhardt, Oliver, Graff, Caroline, Grunblatt, Edna, Hanon, Olivier, Hausner, Lucrezia, Heilmann-Heimbach, Stefanie, Holstege, Henne, Hort, Jakub, Jung, Yoo Jin, Jurgen, Deckert, Kern, Silke, Kuulasmaa, Teemu, Lee, Kun Ho, Lin, Ling, Masullo, Carlo, Mecocci, Patrizia, Mehrabian, Shima, de Mendonca, Alexandre, Boada, Merce, Mir, Pablo, Moebus, Susanne, Moreno, Fermin, Nacmias, Benedetta, Nicolas, Gael, Niida, Shumpei, Nordestgaard, Borge G., Papenberg, Goran, Papma, Janne, Parnetti, Lucilla, Pasquier, Florence, Pastor, Pau, Peters, Oliver, Pijnenburg, Yolande A. L., Pinol-Ripoll, Gerard, Popp, Julius, Porcel, Laura Molina, Jordi Perez-Tur, Raquel Puertaj, Rainero, Innocenzo, Ramakers, Inez, Real, Luis M., Riedel-Heller, Steffi, Rodriguez-Rodriguez, Eloy, Ross, Owen A., Royo, Jose Luis, Rujescu, Dan, Scarmeas, Nikolaos, Scheltens, Philip, Scherbaum, Norbert, Schneider, Anja, Seripa, Davide, Skoog, Ingmar, Solfrizzi, Vincenzo, Spalletta, Gianfranco, Squassina, Alessio, van Swieten, John, Sanchez-Valle, Raquel, Tan, Eng-King, Tegos, Thomas, Teunissen, Charlotte, Thomassen, Jesper Qvist, Tremolizzo, Lucio, Vyhnalek, Martin, Verhey, Frans, Waern, Margda, Wiltfang, Jens, Zhangc, Jing, Zetterberg, Henrik, Blennow, Kaj, He, Zihuai, Williams, Julie, Amouyel, Philippe, Jessen, Frank, Kehoe, Patrick G., Andreassen, Ole A., Van Duin, Cornelia, Tsolaki, Magda, Sanchez-Juan, Pascual, Frikke-Schmidt, Ruth, Sleegers, Kristel, Todau, Tatsushi, Zettergren, Anna, Ingelsson, Martin, Okada, Yukinori, Rossi, Giacomina, Hiltunen, Mikko, Gim, Jungsoo, Ozaki, Kouichi, Sims, Rebecca, Foo, Jia Nee, van der Fliere, Wiesje, Ikeuchi, Takeshi, Ramirez, Alfredo, Mata, Ignacio, Ruiz, Agustin, Gan-Or, Ziv, Lambert, Jean-Charles, Greicius, Michael D., and Mignot, Emmanuel
- Abstract
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1* 04:07, and intermediary with HLA-DRB1* 04:01 and HLA- DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased A beta 42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
- Published
- 2023
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6. Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- Author
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Guen, Yann Le, Guo Luo, Ambati, Aditya, Damotte, Vincent, Jansen, Iris, Eric Yu, Nicolas, Aude, de Rojas, Itziar, Leal, Thiago Peixoto, Miyashita, Akinori, Bellenguez, Céline, Lian, Michelle Mulan, Parveen, Kayenat, Morizono, Takashi, Hyeonseul Park, Grenier-Boley, Benjamin, Tatsuhiko Naito, Küçükali, Fahri, Talyansky, Seth D., and Yogeshwar, Selina Maria
- Subjects
ALZHEIMER'S disease ,PARKINSON'S disease ,HLA histocompatibility antigens ,IMMUNE response ,POST-translational modification - Abstract
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
7. Protective association of HLA‐DRB1*04 subtypes in neurodegenerative diseases implicates acetylated tau PHF6 sequences
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Guen, Yann Le, primary, Luo, Guo, additional, Ambati, Aditya, additional, Damotte, Vincent, additional, Jansen, Iris E, additional, Yu, Eric, additional, Nicolas, Aude, additional, de Rojas, Itziar, additional, Leal, Thiago Peixoto, additional, Miyashita, Akinori, additional, Bellenguez, Céline, additional, Lian, Michelle Mulan, additional, Parveen, Kayenat, additional, Morizono, Takashi, additional, Park, Hyeonseul, additional, Grenier‐Boley, Benjamin, additional, Naito, Tatsuhiko, additional, Küçükali, Fahri, additional, Talyansky, Seth D., additional, Yogeshwar, Selina Marie, additional, Sempere, Vicente, additional, Satake, Wataru, additional, Álvarez‐Martínez, Victoria, additional, Arosio, Beatrice, additional, Belloy, Michael E, additional, Benussi, Luisa, additional, Boland, Anne, additional, Borroni, Barbara, additional, Bullido, María J., additional, Caffarra, Paolo, additional, Clarimon, Jordi, additional, Daniele, Antonio, additional, Darling, Daniel, additional, Debette, Stéphanie, additional, Deleuze, Jean‐François, additional, Dichgans, Martin, additional, Dufouil, Carole, additional, During, Emmanuel, additional, Duzel, Emrah, additional, Galimberti, Daniela, additional, García‐Ribas, Guillermo, additional, García‐Alberca, Jose María, additional, García‐González, Pablo, additional, Giedraitis, Vilmantas, additional, Goldhardt, Oliver, additional, Graff, Caroline, additional, Grunblatt, Edna, additional, Hanon, Olivier, additional, Hausner, Lucrezia, additional, Heilmann‐Heimbach, Stefanie, additional, Holstege, Henne, additional, Hort, Jakub, additional, Jung, Yoo Jin, additional, Jurgen, Deckert, additional, Kern, Silke, additional, Kuulasmaa, Teemu, additional, Lee, Kun Ho, additional, Ling, Ling, additional, Masullo, Carlo, additional, Mecocci, Patrizia, additional, Mehrabian, Shima, additional, de Mendonça, Alexandre, additional, Boada, Mercè, additional, Mir, Pablo, additional, Moebus, Susanne, additional, Moreno, Fermin, additional, Nacmias, Benedetta, additional, Nicolas, Gaël, additional, Niida, Shumpei, additional, Nordestgaard, Børge G., additional, Papenberg, Goran, additional, Papma, Janne M., additional, Parnetti, Lucilla, additional, Pasquier, Florence, additional, Pastor, Pau, additional, Peters, Oliver, additional, Pijnenburg, Yolande A.L., additional, Piñol‐Ripoll, Gerard, additional, Popp, Julius, additional, Molina, Laura, additional, Puerta, Raquel, additional, Pérez‐Tur, Jordi, additional, Rainero, Innocenzo, additional, Real, Luis Miguel, additional, Riedel‐Heller, Steffi G., additional, Rodríguez, Eloy Rodríguez, additional, Royo, José Luís, additional, Rujescu, Dan, additional, Scarmeas, Nikolaos, additional, Scheltens, Philip, additional, Scherbaum, Norbert, additional, Schneider, Anja, additional, Seripa, Davide, additional, Skoog, Ingmar, additional, Solfrizzi, Vincenzo, additional, Spalletta, Gianfranco, additional, Squassina, Alessio, additional, van Swieten, John C, additional, Sanchez‐Valle, Raquel, additional, Tan, Eng‐King, additional, Tegos, Thomas, additional, Teunissen, Charlotte E., additional, Thomassen, Jesper Qvist, additional, Tremolizzo, Lucio, additional, Vyhnalek, Martin, additional, Verhey, Frans R.J., additional, Waern, Margda, additional, Wiltfang, Jens, additional, Zhang, Jing, additional, Zetterberg, Henrik, additional, Blennow, Kaj, additional, Williams, Julie, additional, Amouyel, Philippe, additional, Jessen, Frank, additional, Kehoe, Patrick G, additional, Andreassen, Ole, additional, van Duijn, Cornelia M, additional, Tsolaki, Magda, additional, Sanchez‐Juan, Pascual, additional, Frikke‐Schmidt, Ruth, additional, Sleegers, Kristel, additional, Toda, Tatsushi, additional, Zettergren, Anna, additional, Ingelsson, Martin, additional, Okada, Yukinori, additional, Rossi, Giacomina, additional, Hiltunen, Mikko, additional, Gim, Jungsoo, additional, Ozaki, Kouichi, additional, Sims, Rebecca, additional, Foo, Jia Nee, additional, van der Flier, Wiesje M., additional, Ikeuchi, Takeshi, additional, Ramirez, Alfredo, additional, Mata, Ignacio, additional, Ruiz, Agustin, additional, Gan‐Or, Ziv, additional, Lambert, Jean‐Charles, additional, Greicius, Michael D, additional, and Mignot, Emmanuel, additional
- Published
- 2022
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8. Trans-interaction of risk loci 6p24.1 and 10q11.21 is associated with endothelial damage in coronary artery disease
- Author
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Tay, Kai Yi, primary, Wu, Kan Xing, additional, Chioh, Florence Wen Jing, additional, Autio, Matias Ilmari, additional, Pek, Nicole Min Qian, additional, Narmada, Balakrishnan Chakrapani, additional, Tan, Sock-Hwee, additional, Low, Adrian Fatt-Hoe, additional, Lian, Michelle Mulan, additional, Chew, Elaine Guo Yan, additional, Lau, Hwee Hui, additional, Kao, Shih Ling, additional, Teo, Adrian Kee Keong, additional, Foo, Jia Nee, additional, Foo, Roger Sik Yin, additional, Heng, Chew Kiat, additional, Chan, Mark Yan Yee, additional, and Cheung, Christine, additional
- Published
- 2022
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9. Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes
- Author
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Zheng, Xiaofeng, primary, Ho, Qing Wei Calvin, additional, Chua, Minni, additional, Stelmashenko, Olga, additional, Yeo, Xin Yi, additional, Muralidharan, Sneha, additional, Torta, Federico, additional, Chew, Elaine Guo Yan, additional, Lian, Michelle Mulan, additional, Foo, Jia Nee, additional, Jung, Sangyong, additional, Wong, Sunny Hei, additional, Tan, Nguan Soon, additional, Tong, Nanwei, additional, Rutter, Guy A., additional, Wenk, Markus R., additional, Silver, David L., additional, Berggren, Per-Olof, additional, and Ali, Yusuf, additional
- Published
- 2022
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10. A 3D Fiber‐Hydrogel Based Non‐Viral Gene Delivery Platform Reveals that microRNAs Promote Axon Regeneration and Enhance Functional Recovery Following Spinal Cord Injury
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Zhang, Na, primary, Lin, Junquan, additional, Lin, Vincent Po Hen, additional, Milbreta, Ulla, additional, Chin, Jiah Shin, additional, Chew, Elaine Guo Yan, additional, Lian, Michelle Mulan, additional, Foo, Jia Nee, additional, Zhang, Kunyu, additional, Wu, Wutian, additional, and Chew, Sing Yian, additional
- Published
- 2021
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11. Destabilization of β-cell FIT2 by saturated fatty acids contribute to ER stress and diabetes
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Zheng, Xiaofeng, primary, Ho, Qing Wei Calvin, additional, Chua, Minni, additional, Stelmashenko, Olga, additional, Muralidharan, Sneha, additional, Torta, Federico, additional, Chew, Elaine Guo Yan, additional, Lian, Michelle Mulan, additional, Foo, Jia Nee, additional, Wenk, Markus, additional, Silver, David L., additional, Berggren, Per-Olof, additional, and Ali, Yusuf, additional
- Published
- 2021
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12. Destabilization of β Cell FIT2 by saturated fatty acids alter lipid droplet numbers and contribute to ER stress and diabetes.
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Xiaofeng Zheng, Qing Wei Calvin Ho, Minni Chua, Olga Stelmashenko, Xin Yi Yeo, Muralidharan, Sneha, Torta, Federico, Guo Yan Chew, Elaine, Lian, Michelle Mulan, Jia Nee Foo, Sangyong Jung, Sunny Hei Wong, Nguan Soon Tan, Nanwei Tong, Rutter, Guy A., Wenk, Markus R., Silver, David L., Berggren, Per-Olof, and Ali, Yusuf
- Subjects
SATURATED fatty acids ,UNFOLDED protein response ,CURCUMIN ,COMMERCIAL products ,UNSATURATED fatty acids ,WESTERN diet ,LIPIDS ,LINSEED oil - Abstract
Western-type diets are linked to obesity and diabetes partly because of their high-saturated fatty acid (SFA) content. We found that SFAs, but not unsaturated fatty acids (USFAs), reduced lipid droplets (LDs) within pancreatic ß cells. Mechanistically, SFAs, but not USFAs, reduced LD formation by inducing S-acylation and proteasomal, mediated degradation of fat storage-inducing transmembrane protein 2 (FIT2), an endoplasmic reticulum (ER) resident protein important for LD formation. Targeted ablation of FIT2 reduced ß cell LD numbers, lowered ß cell ATP levels, reduced Ca2+ signaling, dampened vesicle exocytosis, down-regulated ß cell transcription factors, up-regulated unfolded protein response genes, and finally, exacerbated diet-induced diabetes in mice. Subsequent mass spectrometry studies revealed increased C16:0 ceramide accumulation in islets of diet-induced diabetes mice lacking ß cell FIT2. Inhibition of ceramide synthases ameliorated the enhanced ER stress and improved insulin secretion. FIT2 was reduced in mouse diabetic islets, and separately, overexpression of FIT2 increased the number of intracellular LDs and rescued SFA-induced ER stress and apoptosis, thereby highlighting the protective role of FIT2 and LDs against ß cell lipotoxicity. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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13. Association analysis of PSAP variants in Parkinson’s disease patients
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Chao, Yin Xia, primary, Lee, Bernett, additional, Ng, Ebonne Yulin, additional, Lian, Michelle Mulan, additional, Chew, Elaine Guo Yan, additional, Tandiono, Moses, additional, Li, Zheng, additional, Khor, Chiea Chuen, additional, Kumar, Prakash, additional, Tan, Louis C S, additional, Foo, Jia Nee, additional, and Tan, Eng-King, additional
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- 2020
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14. Generation of Human PSC-Derived Kidney Organoids with Patterned Nephron Segments and a De Novo Vascular Network
- Author
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Low, Jian Hui, primary, Li, Pin, additional, Chew, Elaine Guo Yan, additional, Zhou, Bingrui, additional, Suzuki, Keiichiro, additional, Zhang, Tian, additional, Lian, Michelle Mulan, additional, Liu, Meng, additional, Aizawa, Emi, additional, Rodriguez Esteban, Concepcion, additional, Yong, Kylie Su Mei, additional, Chen, Qingfeng, additional, Campistol, Josep M., additional, Fang, Mingliang, additional, Khor, Chiea Chuen, additional, Foo, Jia Nee, additional, Izpisua Belmonte, Juan Carlos, additional, and Xia, Yun, additional
- Published
- 2019
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15. Kidney organoid models reveal cilium-autophagy metabolic axis as a therapeutic target for PKD both in vitroand in vivo
- Author
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Liu, Meng, Zhang, Chao, Gong, Ximing, Zhang, Tian, Lian, Michelle Mulan, Chew, Elaine Guo Yan, Cardilla, Angelysia, Suzuki, Keiichiro, Wang, Huamin, Yuan, Yuan, Li, Yan, Naik, Mihir Yogesh, Wang, Yixuan, Zhou, Bingrui, Soon, Wei Ze, Aizawa, Emi, Li, Pin, Low, Jian Hui, Tandiono, Moses, Montagud, Enrique, Moya–Rull, Daniel, Rodriguez Esteban, Concepcion, Luque, Yosu, Fang, Mingliang, Khor, Chiea Chuen, Montserrat, Nuria, Campistol, Josep M., Izpisua Belmonte, Juan Carlos, Foo, Jia Nee, and Xia, Yun
- Abstract
Human pluripotent stem cell-derived kidney organoids offer unprecedented opportunities for studying polycystic kidney disease (PKD), which still has no effective cure. Here, we developed both in vitroand in vivoorganoid models of PKD that manifested tubular injury and aberrant upregulation of renin-angiotensin aldosterone system. Single-cell analysis revealed that a myriad of metabolic changes occurred during cystogenesis, including defective autophagy. Experimental activation of autophagy via ATG5 overexpression or primary cilia ablation significantly inhibited cystogenesis in PKD kidney organoids. Employing the organoid xenograft model of PKD, which spontaneously developed tubular cysts, we demonstrate that minoxidil, a potent autophagy activator and an FDA-approved drug, effectively attenuated cyst formation in vivo. This in vivoorganoid model of PKD will enhance our capability to discover novel disease mechanisms and validate candidate drugs for clinical translation.
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- 2024
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16. Association analysis of PSAP variants in Parkinson's disease patients.
- Author
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Chao, Yin Xia, Lee, Bernett, Ng, Ebonne Yulin, Lian, Michelle Mulan, Chew, Elaine Guo Yan, Tandiono, Moses, Li, Zheng, Khor, Chiea Chuen, Kumar, Prakash, Tan, Louis C S, Foo, Jia Nee, and Tan, Eng-King
- Subjects
PARKINSON'S disease ,SEQUENCE analysis ,COENZYMES ,GLYCOSIDASES - Published
- 2021
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17. Generation of Human PSC-Derived Kidney Organoids with Patterned Nephron Segments and a De NovoVascular Network
- Author
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Low, Jian Hui, Li, Pin, Chew, Elaine Guo Yan, Zhou, Bingrui, Suzuki, Keiichiro, Zhang, Tian, Lian, Michelle Mulan, Liu, Meng, Aizawa, Emi, Rodriguez Esteban, Concepcion, Yong, Kylie Su Mei, Chen, Qingfeng, Campistol, Josep M., Fang, Mingliang, Khor, Chiea Chuen, Foo, Jia Nee, Izpisua Belmonte, Juan Carlos, and Xia, Yun
- Abstract
Human pluripotent stem cell-derived kidney organoids recapitulate developmental processes and tissue architecture, but intrinsic limitations, such as lack of vasculature and functionality, have greatly hampered their application. Here we establish a versatile protocol for generating vascularized three-dimensional (3D) kidney organoids. We employ dynamic modulation of WNT signaling to control the relative proportion of proximal versus distal nephron segments, producing a correlative level of vascular endothelial growth factor A (VEGFA) to define a resident vascular network. Single-cell RNA sequencing identifies a subset of nephron progenitor cells as a potential source of renal vasculature. These kidney organoids undergo further structural and functional maturation upon implantation. Using this kidney organoid platform, we establish an in vitromodel of autosomal recessive polycystic kidney disease (ARPKD), the cystic phenotype of which can be effectively prevented by gene correction or drug treatment. Our studies provide new avenues for studying human kidney development, modeling disease pathogenesis, and performing patient-specific drug validation.
- Published
- 2019
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18. Multiancestry analysis of the HLA locus in Alzheimer's and Parkinson's diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes.
- Author
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Le Guen Y, Luo G, Ambati A, Damotte V, Jansen I, Yu E, Nicolas A, de Rojas I, Peixoto Leal T, Miyashita A, Bellenguez C, Lian MM, Parveen K, Morizono T, Park H, Grenier-Boley B, Naito T, Küçükali F, Talyansky SD, Yogeshwar SM, Sempere V, Satake W, Alvarez V, Arosio B, Belloy ME, Benussi L, Boland A, Borroni B, Bullido MJ, Caffarra P, Clarimon J, Daniele A, Darling D, Debette S, Deleuze JF, Dichgans M, Dufouil C, During E, Düzel E, Galimberti D, Garcia-Ribas G, García-Alberca JM, García-González P, Giedraitis V, Goldhardt O, Graff C, Grünblatt E, Hanon O, Hausner L, Heilmann-Heimbach S, Holstege H, Hort J, Jung YJ, Jürgen D, Kern S, Kuulasmaa T, Lee KH, Lin L, Masullo C, Mecocci P, Mehrabian S, de Mendonça A, Boada M, Mir P, Moebus S, Moreno F, Nacmias B, Nicolas G, Niida S, Nordestgaard BG, Papenberg G, Papma J, Parnetti L, Pasquier F, Pastor P, Peters O, Pijnenburg YAL, Piñol-Ripoll G, Popp J, Porcel LM, Puerta R, Pérez-Tur J, Rainero I, Ramakers I, Real LM, Riedel-Heller S, Rodriguez-Rodriguez E, Ross OA, Royo LJ, Rujescu D, Scarmeas N, Scheltens P, Scherbaum N, Schneider A, Seripa D, Skoog I, Solfrizzi V, Spalletta G, Squassina A, van Swieten J, Sánchez-Valle R, Tan EK, Tegos T, Teunissen C, Thomassen JQ, Tremolizzo L, Vyhnalek M, Verhey F, Waern M, Wiltfang J, Zhang J, Zetterberg H, Blennow K, He Z, Williams J, Amouyel P, Jessen F, Kehoe PG, Andreassen OA, Van Duin C, Tsolaki M, Sánchez-Juan P, Frikke-Schmidt R, Sleegers K, Toda T, Zettergren A, Ingelsson M, Okada Y, Rossi G, Hiltunen M, Gim J, Ozaki K, Sims R, Foo JN, van der Flier W, Ikeuchi T, Ramirez A, Mata I, Ruiz A, Gan-Or Z, Lambert JC, Greicius MD, and Mignot E
- Subjects
- Humans, Histocompatibility Antigens, HLA Antigens, Alzheimer Disease genetics, HLA-DRB1 Chains genetics, Parkinson Disease genetics
- Abstract
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
- Published
- 2023
- Full Text
- View/download PDF
19. Association analysis of PSAP variants in Parkinson's disease patients.
- Author
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Chao YX, Lee B, Ng EY, Lian MM, Chew EGY, Tandiono M, Li Z, Khor CC, Kumar P, Tan LCS, Foo JN, and Tan EK
- Subjects
- Genome-Wide Association Study, Glucosylceramidase, Humans, Parkinson Disease, Saposins
- Published
- 2021
- Full Text
- View/download PDF
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