Article
Biochemistry & Molecular Biology
Maya Maor-Nof, Zohar Shipony, Rodrigo Lopez-Gonzalez, Lisa Nakayama, Yong-Jie Zhang, Julien Couthouis, Jacob A. Blum, Patricia A. Castruita, Gabriel R. Linares, Kai Ruan, Gokul Ramaswami, David J. Simon, Aviv Nof, Manuel Santana, Kyuho Han, Nasa Sinnott-Armstrong, Michael C. Bassik, Daniel H. Geschwind, Marc Tessier-Lavigne, Laura D. Attardi, Thomas E. Lloyd, Justin K. Ichida, Fen-Biao Gao, William J. Greenleaf, Jennifer S. Yokoyama, Leonard Petrucelli, Aaron D. Gitler
Summary: The repeat expansion in the C9orf72 gene leads to activation of a specific transcriptional program, causing neurodegeneration. Removing p53 in experiments successfully rescued neuronal degeneration and extended survival.
Article
Neurosciences
Karim S. Ibrahim, Salah El Mestikawy, Khaled S. Abd-Elrahman, Stephen S. G. Ferguson
Summary: Huntington's disease (HD) is a neurodegenerative disease characterized by motor and cognitive impairments. The role of vesicular glutamate transporter-3 (VGLUT3) in HD pathophysiology is unclear. This study found that VGLUT3 deletion rescued motor and cognitive deficits in HD mouse models, likely through the activation of Akt and ERK1/2 pathways. These findings suggest that VGLUT3 could be a potential target for HD therapeutics.
JOURNAL OF NEUROSCIENCE
(2023)
Article
Biology
Rubika Balendra, Igor Ruiz de los Mozos, Hana M. Odeh, Idoia Glaria, Carmelo Milioto, Katherine M. Wilson, Agnieszka M. Ule, Martina Hallegger, Laura Masino, Stephen Martin, Rickie Patani, James Shorter, Jernej Ule, Adrian M. Isaacs
Summary: An intronic GGGGCC repeat expansion in C9orf72 is a common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Poly(GA), poly(GR), and poly(PR) dipeptide repeat proteins generated from the repeats are implicated in neurodegeneration. In this study, we performed CLIP analysis and found that poly(PR) binds to nearly 600 RNAs, with enrichment of the sequence GAAGA at the binding sites. In vitro experiments showed that poly(GAAGA) RNA has a higher affinity for poly(PR) and induces its phase separation into condensates.
LIFE SCIENCE ALLIANCE
(2023)
Article
Cell Biology
Eric Hendricks, Alicia M. Quihuis, Shu-Ting Hung, Jonathan Chang, Nomongo Dorjsuren, Balint Der, Kim A. Staats, Yingxiao Shi, Naomi S. Sta Maria, Russell E. Jacobs, Justin K. Ichida
Summary: This study reveals that a genetic mutation, C9ORF72 repeat expansion, not only restricts neural stem cell proliferation and reduces cortical and thalamic size in utero, but also impairs neurodevelopment through the expression of a repeat expansion-derived dipeptide repeat protein (DPR). Pharmacological simulation of the effects of the repeat expansion on neurodevelopment increases susceptibility to motor defects in C9ORF72 mice. This research highlights the importance of understanding the impact of genetic mutations on neurodevelopment in the onset of neurodegenerative diseases.
Article
Clinical Neurology
Wenting Guo, Haibo Wang, Arun Kumar Tharkeshwar, Julien Couthouis, Elke Braems, Pegah Masrori, Evelien Van Schoor, Yannan Fan, Karan Ahuja, Matthieu Moisse, Maarten Jacquemyn, Rodrigo Furtado Madeiro da Costa, Madhavsai Gajjar, Sriram Balusu, Tine Tricot, Laura Fumagalli, Nicole Hersmus, Rekin's Janky, Francis Impens, Pieter Vanden Berghe, Ritchie Ho, Dietmar Rudolf Thal, Rik Vandenberghe, Muralidhar L. Hegde, Siddharthan Chandran, Bart De Strooper, Dirk Daelemans, Philip Van Damme, Ludo Van den Bosch, Catherine Verfaillie
Summary: In this study, we identified NEK6 as a novel therapeutic target for C9orf72 FTD/ALS by performing a kinome-wide CRISPR/Cas9 knock-out screen in human induced pluripotent stem cell-derived cortical neurons. NEK6 was found to regulate poly(PR)-mediated p53-related DNA damage.
ALZHEIMERS & DEMENTIA
(2023)
Review
Cell Biology
Kohsuke Kanekura, Yuhei Hayamizu, Masahiko Kuroda
Summary: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap genetically and pathologically, with hexanucleotide expansions in the C9ORF72 gene being a leading cause. Arginine-rich dipeptide repeat proteins (DRPs) play a role in ALS pathogenesis through molecular interactions.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2022)
Article
Cell Biology
Chen Chen, Yoshiaki Yamanaka, Koji Ueda, Peiying Li, Tamami Miyagi, Yuichiro Harada, Sayaka Tezuka, Satoshi Narumi, Masahiro Sugimoto, Masahiko Kuroda, Yuhei Hayamizu, Kohsuke Kanekura
Summary: The pathogenicity of R-rich DPRs is primarily mediated by disrupting and trapping proteins through LLPS, which is controlled by the distribution of charged Arg residues.
JOURNAL OF CELL BIOLOGY
(2021)
Article
Neurosciences
Lizhu Xu, Dan Wang, Lu Zhao, Zhengsheng Yang, Xu Liu, Xinyue Li, Tingli Yuan, Ye Wang, Tianzhuang Huang, Ning Bian, Yuqun He, Xinglong Chen, Baohong Tian, Zexian Liu, Fucheng Luo, Wei Si, Guangping Gao, Weizhi Ji, Yuyu Niu, Jingkuan Wei
Summary: This study demonstrates that the Poly(PR) protein, resulting from the expanded G4C2 repeats in the C9orf72 gene, can independently induce neurodegeneration associated with C9-ALS/FTD, providing new insights into the pathogenesis of these diseases.
NEUROBIOLOGY OF DISEASE
(2023)
Article
Multidisciplinary Sciences
Anna B. Loveland, Egor Svidritskiy, Denis Susorov, Soojin Lee, Alexander Park, Sarah Zvornicanin, Gabriel Demo, Fen-Biao Gao, Andrei A. Korostelev
Summary: This study reveals the structural mechanism of how poly-GR and poly-PR inhibit translation and may perturb ribosome assembly.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Yixin Wang, Liu Liu, Hui Chen, Yinxue Yang, Chenchen Mu, Haigang Ren, Yanli Liu, Liqiang Yu, Qi Fang, Guanghui Wang, Zongbing Hao
Summary: This study identified severe DNA damage caused by poly-PR and its interaction with the ALS-related FUS protein, suggesting a potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.
HUMAN MOLECULAR GENETICS
(2023)
Article
Multidisciplinary Sciences
Yunhee Jo, Jiwon Lee, Seul-Yi Lee, Ilmin Kwon, Hana Cho
Summary: Expansion of the GGGGCC hexanucleotide repeat in the C9orf72 gene is a common genetic cause of ALS. This study shows that proline-arginine poly-dipeptides generated from the C9orf72 repeat expansions increase excitability in motor cortex pyramidal neurons by enhancing the persistent sodium current primarily through the Nav1.2-beta 1-beta 4 complex. The PR poly-dipeptides bind more strongly to Nav1.2 in the motor cortex, suggesting a cellular mechanism underlying cortical hyperexcitability in C9orf72 ALS.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Multidisciplinary Sciences
Hamidreza Jafarinia, Erik Van der Giessen, Patrick R. Onck
Summary: Poly-PR can bind with multiple importins and exportins, interfering with various important steps involved in nucleocytoplasmic transport, including cargo binding, release, and protein transport.
SCIENTIFIC REPORTS
(2022)
Article
Biophysics
Size Zheng, Ali Sahimi, Katherine S. Shing, Muhammad Sahimi
Summary: The study found that during aggregation, poly-proline-arginine (poly-PR) forms a double-helix structure while poly-glycine-arginine (poly-GR) does not form stable aggregates, indicating the latter is less likely to aggregate. The hydrophilic arginine residues within their structures make poly-PR and poly-GR less likely to aggregate, but may facilitate DPR protein migration and activation of neurons, leading to neuronal death.
BIOPHYSICAL JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Fumin Yang, Yacoubou Abdoul Razak Mahaman, Bin Zhang, Jian-Zhi Wang, Rong Liu, Fei Liu, Xiaochuan Wang
Summary: C9orf72-derived dipeptide repeats (DPRs) proteins, specifically poly-proline-arginine (poly-PR), contribute to the neurodegeneration in C9-ALS/FTD by inducing neuronal damage, p53 accumulation and activation, and impairment of the ubiquitin-proteasome system. Poly-PR stabilizes p53 by reducing mdm2-p53 interactions and preventing p53 degradation. Inhibition of the poly-PR binding to p53 may have therapeutic potential for C9-ALS/FTD treatment.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Clinical Neurology
Katherine M. Wilson, Eszter Katona, Idoia Glaria, Mireia Carcole, Imogen J. Swift, Aitana Sogorb-Esteve, Carolin Heller, Arabella Bouzigues, Amanda J. Heslegrave, Ashvini Keshavan, Kathryn Knowles, Saurabh Patil, Susovan Mohapatra, Yuanjing Liu, Jaya Goyal, Raquel Sanchez-Valle, Robert Laforce, Matthis Synofzik, James B. Rowe, Elizabeth Finger, Rik Vandenberghe, Christopher R. Butler, Alexander Gerhard, John C. Van Swieten, Harro Seelaar, Barbara Borroni, Daniela Galimberti, Alexandre de Mendonca, Mario Masellis, M. Carmela Tartaglia, Markus Otto, Caroline Graff, Simon Ducharme, Jonathan M. Schott, Andrea Malaspina, Henrik Zetterberg, Ramakrishna Boyanapalli, Jonathan D. Rohrer, Adrian M. Isaacs
Summary: This study developed a highly sensitive and robust immunoassay for measuring poly(GP) dipeptide repeat proteins in the cerebrospinal fluid of patients with C9orf72-associated FTD/ALS. The assay showed 100% specificity and sensitivity, and is suitable for use in clinical trials to determine target engagement.
JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
(2022)
Review
Neurosciences
Rui Wang, Haigang Ren, Elena Kaznacheyeva, Xiaojun Lu, Guanghui Wang
Summary: This article provides an overview of the role of glia and alpha-syn pathology in the pathogenesis of Parkinson's disease (PD), highlighting the relationships between glial responses and the spread of alpha-syn pathology.
NEUROSCIENCE BULLETIN
(2023)
Article
Chemistry, Multidisciplinary
Hong-yang Sun, Jin Wu, Rui Wang, Shun Zhang, Hao Xu, Elena Kaznacheyeva, Xiao-jun Lu, Hai-gang Ren, Guang-hui Wang
Summary: Parkinson's disease (PD) is characterized by the loss of dopaminergic neurons and the accumulation of Lewy bodies in the substantia nigra. Microglia-mediated neuroinflammation plays a key role in PD pathogenesis. In this study, we found that pazopanib, a pan-VEGF receptor tyrosine kinase inhibitor, showed anti-inflammatory and neuroprotective effects in PD models.
ACTA PHARMACOLOGICA SINICA
(2023)
Editorial Material
Neurosciences
Hongyang Sun, Guanghui Wang
NEUROSCIENCE BULLETIN
(2023)
Editorial Material
Geriatrics & Gerontology
Rui Wang, Haigang Ren, Li-Fang Hu, Ning Song, Ling Long, Zili You, Guanghui Wang
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Clinical Neurology
Xuebing Ding, Yongkang Chen, Cancan Guo, Yu Fu, Chi Qin, Qingyong Zhu, Jiuqi Wang, Rui Zhang, Haiyan Tian, Renyi Feng, Han Liu, Dongxiao Liang, Guanghui Wang, Junfang Teng, Jinchen Li, Beisha Tang, Xuejing Wang
Summary: This research report identifies that mutations in the ARHGEF15 gene are a cause of cerebral small vessel disease (CSVD), and individuals with these mutations also exhibit osteoporosis and fractures.
ACTA NEUROPATHOLOGICA
(2023)
Article
Chemistry, Multidisciplinary
Le-le Liu, Yu Han, Zi-jia Zhang, Yi-qi Wang, Yu-wei Hu, Elena Kaznacheyeva, Jian-qing Ding, Dong-kai Guo, Guang-hui Wang, Bin Li, Hai-gang Ren
Summary: Parkinson's disease is a neurodegenerative motor disorder characterized by reduced dopamine levels. The loss of DJ-1 function leads to increased expression of MAO-B, which is associated with dopamine degradation, oxidative stress, and mitochondrial dysfunction. This study reveals the mechanistic link between DJ-1 and MAO-B expression and contributes to understanding the pathogenesis of Parkinson's disease.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Multidisciplinary Sciences
Ya-jing Liu, Yu Ding, Yan-qing Yin, Hui Xiao, Gang Hu, Jia-wei Zhou
Summary: Cspg4high microglia, characterized by unique transcriptomic signature, are one of the origins of microgliosis during neurodegeneration. They can proliferate in response to pathological alpha-synuclein stimulation, and show higher survival rates in transplantation therapy. Additionally, these cells are detected in the brain of AD patients, suggesting their involvement in AD pathogenesis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Yixin Wang, Liu Liu, Hui Chen, Yinxue Yang, Chenchen Mu, Haigang Ren, Yanli Liu, Liqiang Yu, Qi Fang, Guanghui Wang, Zongbing Hao
Summary: This study identified severe DNA damage caused by poly-PR and its interaction with the ALS-related FUS protein, suggesting a potential therapeutic role of FUS in alleviating poly-PR-induced cell toxicity.
HUMAN MOLECULAR GENETICS
(2023)
Article
Cell Biology
Xingyun Xu, Hang Zhou, Hainan Wu, Zhigang Miao, Bo Wan, Haigang Ren, Wei Ge, Guanghui Wang, Xingshun Xu
Summary: The lateral habenula (LHb) is known to affect social behaviors, but its role in regulating social interaction is unclear. This study demonstrates that the methylase Tet2 is highly expressed in the LHb and its deficiency leads to impaired social preference in mice. Replenishing Tet2 in the LHb can rescue this impairment, suggesting that Tet2 in the LHb may be a therapeutic target for social behavior deficits.
Article
Multidisciplinary Sciences
Jin Wu, Yingying Han, Hao Xu, Hongyang Sun, Rui Wang, Haigang Ren, Guanghui Wang
Summary: This study investigates the role of chaperone-mediated autophagy (CMA) in neuroinflammation and its impact on microglia activation and neuronal damage. The researchers found that CMA activation can inhibit microglial activation and inflammation through the p300-associated NF-kappa B signaling pathway. Additionally, they demonstrated that CMA dysfunction worsens microglial activation and inflammation. These findings provide insight into the mechanistic link between CMA and neuroinflammation.
