Review
Pharmacology & Pharmacy
Sonia Azeggagh, Daniel C. Berwick
Summary: Current therapeutic approaches for Parkinson's disease focus on symptom relief rather than disease progression. Inhibition of LRRK2 function is a promising strategy due to its role in familial and idiopathic Parkinson's disease. Progress has been made in finding effective LRRK2 inhibitors, but the complexity of LRRK2 presents challenges and opportunities for unintended consequences. Multiple molecules are in clinical trials, providing cause for optimism in the search for alternative treatment options.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Multidisciplinary Sciences
Mateusz Dyla, Nicolas S. Gonzalez Foutel, Daniel E. Otzen, Magnus Kjaergaard
Summary: This study investigates how the affinity of docking interactions in kinases affects enzymatic activity and how to choose the optimal docking module to complement a given substrate. Equations predicting the optimal binding strength of a kinase docking interaction were developed and validated using numerical simulations and steady-state phosphorylation kinetics.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Medicinal
Scott H. Henderson, Fiona Sorrell, James Bennett, Oleg Fedorov, Marcus T. Hanley, Paulo H. Godoi, Roberta Ruela de Sousa, Sean Robinson, Alexander Ashall-Kelly, Iva Hopkins Navratilova, Daryl S. Walter, Jonathan M. Elkins, Simon E. Ward
Summary: DYRK1A plays a crucial role in regulating the proliferation and differentiation of neuronal progenitor cells, making it a potential target for the treatment of neurodegenerative diseases and diabetes. The development of pyrazolo[1,5-b]pyridazin inhibitors with good physicochemical properties and selectivity over the kinome has opened up new possibilities for the discovery of therapies targeting DYRK1A function. Compound 11 demonstrated promising permeability and cellular activity, positioning it as a potential candidate for in vivo studies.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Paige Grant, Jitendra Kumar, Satyabrata Kar, Michael Overduin
Summary: The study investigated the effects of two specific kinase inhibitors for CaMK1D on A beta-mediated toxicity in mouse primary cortical neurons. While these inhibitors were able to prevent A beta-induced tau hyperphosphorylation, they were not able to protect cells from A beta induced toxicity. Further research and development may lead to the potential use of these inhibitors as part of a multi-drug strategy to combat Alzheimer's disease.
Article
Neurosciences
Xingfeng Xu, Mao Li, Yan Su, Qi Wang, Peifang Qin, Haitao Huang, Yuting Zhang, Yali Zhou, Jianguo Yan
Summary: This article aimed to explore the potential mechanism of C9orf72 involved in the pathogenesis of Parkinson's disease (PD). The study found that the expression level of C9orf72 protein was significantly reduced in PD models, while the mRNA expression level remains unchanged. The degradation of C9orf72 protein was mainly through the ubiquitin-proteasome pathway, and its phosphorylation at the S9 site promoted its degradation. Knockdown of C9orf72 aggravated autophagy dysfunction and increased neuronal loss and motor dysfunction in PD mice, while overexpression of C9orf72 alleviated autophagy dysfunction in PD neurons. Interfering with Cdk5 phosphorylation at the S9 site of C9orf72 could alleviate autophagy dysfunction, neuronal death, and motor dysfunction caused by C9orf72 protein degradation.
CNS NEUROSCIENCE & THERAPEUTICS
(2023)
Article
Pharmacology & Pharmacy
Hariharan Saminathan, Anamitra Ghosh, Danhui Zhang, Chunjuan Song, Huajun Jin, Vellareddy Anantharam, Arthi Kanthasamy, Anumantha G. Kanthasamy
Summary: The study reveals that Fyn kinase plays a crucial role in the degeneration of dopaminergic neurons in Parkinson's disease by activating the apoptotic signaling cascade through PKC delta phosphorylation. Inhibitors targeting Fyn activation could potentially be a novel therapeutic approach to delay or prevent selective degeneration of dopaminergic neurons in PD.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Mutsuki Amano, Yoko Kanazawa, Kei Kozawa, Kozo Kaibuchi
Summary: This study analyzed the interaction between Rho-kinase and MYPT1 and found that three short regions of MYPT1 close to the phosphorylation sites are crucial for the interaction with Rho-kinase. The phosphorylation levels of MYPT1 without these regions were reduced and only affected neighboring phosphorylation sites. Furthermore, the combination of pseudosubstrate (PS) and docking motifs (DMs) of MYPT1 was found to be a potent inhibitor of Rho-kinase.
Article
Biochemistry & Molecular Biology
Mohd Amir, Saleem Javed
Summary: This study evaluated the binding relationship between TPT and HSA, and found that the interaction between TPT and HSA triggered a static fluorescence quenching process. TPT preferred binding to site III of HSA, inducing conformational changes and reducing alpha-helical content. Additionally, TPT enhanced protein stability in the temperature range of 20 to 90 degrees C. The findings provide a clear picture of the impacts of TPT on HSA interaction.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Review
Biochemistry & Molecular Biology
Zhengkun Zhang, Lang Bu, Junhang Luo, Jianping Guo
Summary: The article summarizes the important roles of protein kinases in modulating immune checkpoints in tumor and immune cells, and highlights the promising clinical outcomes achieved by the combination of ICIs with kinase inhibitors in various cancer types.
BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER
(2022)
Article
Pharmacology & Pharmacy
Qi Wang, Bixi Tang, Dandan Sun, Ying Dong, Yinchun Ji, Huanyu Shi, Liwei Zhou, Yueyue Yang, Menglan Luo, Qian Tan, Lin Chen, Yue Dong, Cong Li, Rongrong Xie, Yi Zang, Jingkang Shen, Bing Xiong, Jia Li, Danqi Chen
Summary: Idiopathic pulmonary fibrosis (IPF) is a serious chronic lung disease with inaccurate diagnosis, limited clinical therapy, and high mortality. The discoidin domain receptors (DDR) have been identified as promising drug targets for IPF treatment, and compound 47 shows potential as a candidate for further drug development.
ACTA PHARMACEUTICA SINICA B
(2022)
Article
Plant Sciences
Shih-Chung Yen, Yi-Wen Wu, Cheng-Chiao Huang, Min-Wu Chao, Huang-Ju Tu, Liang-Chieh Chen, Tony Eight Lin, Tzu-Ying Sung, Hui-Ju Tseng, Jung-Chun Chu, Wei-Jan Huang, Chia-Ron Yang, Wei-Chun HuangFu, Shiow-Lin Pan, Kai-Cheng Hsu
Summary: This study evaluated the anticancer effects of flavonoid compounds collected from an in-house library and investigated their potential anticancer mechanisms by targeting multiple kinases for inhibition in AML cells.
Article
Geriatrics & Gerontology
Liang Feng, Haijun He, Xi Xiong, Kai Xia, Shuangjie Qian, Qianqian Ye, Feifei Feng, Shuoting Zhou, Xianchai Hong, Yiming Liu, Chenglong Xie
Summary: This study found that plasma PGAM5 can serve as an independent biomarker for Parkinson's disease, especially in elderly patients over the age of 60 and patients without hypertension. Combining PGAM5 with other indicators can improve its predictive utility.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Ranjan K. Singh, Ahmed Soliman, Giambattista Guaitoli, Eliza Stoermer, Felix von Zweydorf, Thomas Dal Maso, Asmaa Oun, Laura Van Rillaer, Sven H. Schmidt, Deep Chatterjee, Joshua A. David, Els Pardon, Thomas U. Schwartz, Stefan Knapp, Eileen J. Kennedy, Jan Steyaert, Friedrich W. Herberg, Arjan Kortholt, Christian Johannes Gloeckner, Wim Versees
Summary: Mutations in the LRRK2 gene are a leading cause of Parkinson's disease, while overactivation of LRRK2 is associated with idiopathic form of the disease. Researchers have identified and characterized nanobodies that can bind to different domains of LRRK2 and inhibit or activate its activity. These nanobodies act through an allosteric inhibitor mechanism and provide potential therapeutic strategies for Parkinson's disease.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Biochemistry & Molecular Biology
Digambar B. Yevale, Nishith Teraiya, Twinkle D. Lalwani, Rakesh Kumar Ameta, Chetan B. Sangani
Summary: In this study, a novel pyrazole compound substituted at the 4th position was designed, synthesized, and evaluated for its cytotoxicity against cancer cells and inhibition of Aurora-A kinase. Compound 5h and 5e showed high cytotoxicity against MCF-7 and MDA-MB-231 cells and displayed strong inhibition of Aurora-A kinase. These findings suggest that compounds 5h and 5e may have potential as anticancer agents.
BIOORGANIC CHEMISTRY
(2023)
Article
Geriatrics & Gerontology
Qi Su, Wei Lun Ng, Suh Yee Goh, Muhammad Yaaseen Gulam, Lin-Fa Wang, Eng-King Tan, Matae Ahn, Yin-Xia Chao
Summary: This article discusses the relationship between key proteins and inflammasome activation in Parkinson's disease, as well as promising inhibitors of the NLRP3 inflammasome pathway as potential therapies. It also provides a summary of current and potential in vitro and in vivo models for therapeutic discovery and development.
FRONTIERS IN AGING NEUROSCIENCE
(2022)
Article
Oncology
Shauni Lien Geeraerts, Kim Rosalie Kampen, Gianmarco Rinaldi, Purvi Gupta, Melanie Planque, Nikolaos Louros, Elien Heylen, Kaat De Cremer, Katrijn De Brucker, Stijn Vereecke, Benno Verbelen, Pieter Vermeersch, Joost Schymkowitz, Frederic Rousseau, David Cassiman, Sarah-Maria Fendt, Arnout Voet, Bruno P. A. Cammue, Karin Thevissen, Kim De Keersmaecker
Summary: Metabolic rewiring in cancer cells often leads to dependency on intracellular serine/glycine synthesis. This study repurposed the drugs sertraline and thimerosal to selectively target serine/glycine synthesis-addicted breast cancer and T-cell acute lymphoblastic leukemia cells. The combination of sertraline and mitochondrial inhibitors showed promising antitumor activity by inhibiting serine/glycine synthesis and mitochondrial metabolism simultaneously.
MOLECULAR CANCER THERAPEUTICS
(2021)
Article
Biochemistry & Molecular Biology
Yenthel Verhaegen, Libao Liu, Tien T. Nguyen, Tom Van Loy, Arnout R. D. Voet, Dominique Schols, Wim Dehaen, Steven De Jonghe
Summary: A diverse library of compounds was synthesized through various reactions on a bromo-naphthalene precursor, and demonstrated CCR8 antagonistic properties in experiments, with decreased activity possibly explained by homology molecular modeling.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Laurens Vandebroek, Hiroki Noguchi, Alexander Anyushin, Luc Van Meervelt, Arnout R. D. Voet, Tatjana N. Parac-Vogt
Summary: This study reports the hierarchical self-assembly of hybrid bioinorganic structures through specific and tailored interactions. A supramolecular assembly was formed between the designer protein Pizza6-S (Pizza6) and the polyoxometalate (POM) {K3Cu3(NO3)[A-alpha-PW9O34](2)}. The crystal structure revealed the dissociation and reassembly of Cu3 with the protein to form a novel POM-protein cage. Spectroscopic characterization of the Pizza6/Cu3 solution suggests that the dissociation of Cu3 is facilitated by the synergistic effect of six histidine residues, resulting in the formation of the hierarchical supramolecular assembly.
CRYSTAL GROWTH & DESIGN
(2022)
Article
Biochemistry & Molecular Biology
Christine Helsen, Tien Nguyen, Thomas Vercruysse, Staf Wouters, Dirk Daelemans, Arnout Voet, Frank Claessens
Summary: This study identifies a gain-of-function mutation in AR LBD, T850D, which enhances AR activity. The study also reveals the details of allosteric communications within the LBD.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Roy Eerlings, Nana Barbakadze, Tien Nguyen, Nanuli Nadaraia, Elien Smeets, Lisa Moris, Florian Handle, Sarah El Kharraz, Wout Devlies, Arnout Voet, Wim Dehaen, Frank Claessens, Christine Helsen
Summary: The development of a novel luciferase reporter assay, termed SRi-Luc, allows for the examination of small-molecule interactions on all steroid receptors. Triazolized steroidal compounds developed through this method showed potential cross-reactivity with other receptors, despite being selected as antiandrogens.
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
(2022)
Article
Cell Biology
Antoine Marchand, Alessia Sarchione, Panagiotis S. Athanasopoulos, Helene Bauderlique-Le Roy, Liesel Goveas, Romain Magnez, Matthieu Drouyer, Marco Emanuele, Franz Y. Ho, Maxime Liberelle, Patricia Melnyk, Nicolas Lebegue, Xavier Thuru, R. Jeremy Nichols, Elisa Greggio, Arjan Kortholt, Thierry Galli, Marie-Christine Chartier-Harlin, Jean-Marc Taymans
Summary: The study investigates the functional consequences of phosphorylation or dephosphorylation of the Leucine Rich Repeat Kinase 2 (LRRK2) gene, a major genetic determinant of Parkinson's disease. The results suggest that phosphorylation of LRRK2 is associated with healthy phenotypes, while dephosphorylation is associated with phenotypes associated with Parkinson's disease pathology.
Article
Geriatrics & Gerontology
Elien Smeets, Shengyun Huang, Xiao Yin Lee, Erika Van Nieuwenhove, Christine Helsen, Florian Handle, Lisa Moris, Sarah El Kharraz, Roy Eerlings, Wout Devlies, Mathijs Willemsen, Leoni Bucken, Teresa Prezzemolo, Stephanie Humblet-Baron, Arnout Voet, Anne Rochtus, Ann Van Schepdael, Francis de Zegher, Frank Claessens
Summary: A mutation in the CYP4F3 gene is associated with clinical features related to inflammation. The mutation leads to reduced activity of CYP4F3 and decreased metabolism of leukotriene B4 in the immune system. This finding contributes to our understanding of the pathogenesis of immune disorders and provides new insights for future treatment strategies.
JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE
(2022)
Article
Oncology
Christine Helsen, Tien T. Nguyen, Xiao Yin Lee, Roy Eerlings, Nikolaos Louros, Joost Schymkowitz, Frederic Rousseau, Frank Claessens, Arnout Voet
Summary: A new binding site, the DIM pocket, has been identified for AR inhibitors, with DIM20 family compounds showing potential anti-prostate cancer effects by inhibiting AR activity and dimerization.
MOLECULAR CANCER THERAPEUTICS
(2022)
Article
Plant Sciences
John Vaughan-Hirsch, Dongdong Li, Albert Roig Martinez, Stijn Roden, Jolien Pattyn, Shu Taira, Hitomi Shikano, Yoko Miyama, Yukari Okano, Arnout Voet, Bram van de Poel
Summary: Plants produce the hormone ethylene to regulate developmental processes and stress responses. This study reveals the biological function of an uncharacterized ethylene precursor dipeptide, which can be absorbed and converted to ethylene by Arabidopsis, thus increasing ethylene production levels and inducing ethylene responses.
FRONTIERS IN PLANT SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Francesca Di Leva, Michele Filosi, Lisa Oyston, Erica Silvestri, Anne Picard, Alexandros A. Lavdas, Evy Lobbestael, Veerle Baekelandt, G. Gregory Neely, Peter P. Pramstaller, Andrew A. Hicks, Corrado Corti
Summary: Autosomal dominant mutations in the gene encoding alpha-synuclein (SNCA) were the first to be linked with hereditary Parkinson's disease (PD). Duplication and triplication of SNCA has been observed in PD patients, together with mutations at the N-terminal of the protein, among which A30P and A53T influence the formation of fibrils. Our data show that the expression of alpha-synuclein and ITPKB is correlated in pathological situations, as observed in SK-N-SH cells and cortex from PD patients.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Multidisciplinary Sciences
Tess Dierckx, Sam Vanherle, Mansour Haidar, Elien Grajchen, Fleur Mingneau, Pascal Gervois, Esther Wolfs, Dany Bylemans, Arnout Voet, Tien Nguyen, Ibrahim Hamad, Markus Kleinewietfeld, Jeroen F. J. Bogie, Jerome J. A. Hendriks
Summary: This study reveals the reasons for the failure of remyelination, including the overly inflammatory microenvironment and the intrinsic inability of oligodendrocyte precursor cells to differentiate. The study also shows that phloretin can significantly promote remyelination by acting on the nuclear receptor peroxisome proliferator-activated receptor gamma to promote the maturation of oligodendrocyte precursor cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Clinical Neurology
Diego Cabezudo, George Tsafaras, Eva Van Acker, Chris Van den Haute, Veerle Baekelandt
Summary: This study provides evidence for the central role of LRRK2 protein in gut inflammation and Parkinson's disease. The G2019S mutation in LRRK2 increases inflammatory response and disease phenotype. The study also shows that gut inflammation can impact brain homeostasis and contribute to neurodegeneration in Parkinson's disease.
ACTA NEUROPATHOLOGICA
(2023)
Article
Biochemistry & Molecular Biology
Christine Helsen, Maria Santa Rocca, Tien T. Nguyen, Roy Eerlings, Xiao Yin Lee, Sofie De Block, Cinzia Vinanzi, Francesco Di Millo, Vito Giagulli, Arnout Voet, Alberto Ferlin, Frank Claessens
Summary: We discovered the missense mutation V770D in the androgen receptor of two sisters with complete androgen insensitivity. The mutation resulted in transcriptional inactivity and impaired dimerization and ligand binding affinity. We found that the AR LBD dimer structure could be better described by a GR-like LBD dimer model, and the V770 residue played a key role in the stability of this dimer.
Article
Multidisciplinary Sciences
Sam Balzarini, Roosje Van Ende, Arnout Voet, Koen Geuten
Summary: Despite progress in methodology, a widely applicable, easily scalable, and cost-effective procedure for isolating specific RNPs is still lacking. We present the Silica-based Acidic Phase Separation (SAPS)-capture workflow, which combines previously described techniques in a versatile, optimal, and cost-effective protocol. This method isolates specific RNPs from pre-purified samples, resulting in an increased RNP/bead ratio and reduced experimental cost. Validation experiments were conducted using yeast and Arabidopsis, demonstrating the applicability of this procedure to study the ribonome of any RNA molecule in any organism or tissue type.
SCIENTIFIC REPORTS
(2023)
Article
Neurosciences
Julia Obergasteiger, Anne-Marie Castonguay, Sara Pizzi, Stefano Magnabosco, Giulia Frapporti, Evy Lobbestael, Veerle Baekelandt, Andrew A. Hicks, Peter P. Pramstaller, Claude Gravel, Corrado Corti, Martin Levesque, Mattia Volta
Summary: In Parkinson's disease, the accumulation of misfolded alpha-synuclein in the substantia nigra leads to the loss of dopaminergic neurons. The exact mechanisms behind this pathology are still unclear, but it is believed to involve the autophagy-lysosome pathway. LRRK2 mutations, a major cause of both familial and sporadic PD, have been shown to affect the modulation of aSyn inclusion. The downregulation of the PD risk factor RIT2 rescued abnormalities in the autophagy-lysosome pathway and reduced aSyn aggregations, suggesting that targeting RIT2 could be a potential strategy for treating familial and idiopathic PD.
NPJ PARKINSONS DISEASE
(2023)