Review
Biochemistry & Molecular Biology
Maria Dolores Perez-Carrion, Inmaculada Posadas, Javier Solera, Valentin Cena
Summary: This review summarizes the main pathological mutations in LRRK2 that contribute to Parkinson's disease and discusses the different cellular and therapeutic strategies to correct LRRK2 homeostasis.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(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)
Review
Biochemistry & Molecular Biology
Jasmin Galper, Woojin S. Kim, Nicolas Dzamko
Summary: Genetic alterations in the LRRK2 gene are a common risk factor for Parkinson's disease. LRRK2 alterations are associated with changes in lipid pathways, which can lead to cellular pathology.
Review
Genetics & Heredity
Gunjan Thakur, Vikas Kumar, Keun Woo Lee, Chungkil Won
Summary: Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the midbrain. Mutations in the gene encoding LRRK2 have been identified as potential therapeutic targets for PD. Therefore, the search for LRRK2 inhibitors has become the focus of drug discovery, and various investigations have been conducted to study its mechanism and develop inhibitors.
Review
Medicine, General & Internal
Xiao-Yan Yao, Li-Na Guan, Qi Chen, Chao Ren
Summary: The pathogenesis of Parkinson's disease involves multiple factors such as heredity, environment, and ageing. Mutations in LRRK2 are recognized as risk factors and play a significant role in the degeneration of dopaminergic neurons in PD. Glial hyperactivation-mediated neuroinflammation is also involved in the development of PD.
POSTGRADUATE MEDICAL JOURNAL
(2023)
Article
Cell Biology
Sara R. Oliveira, Pedro A. Dionisio, Maria M. Gaspar, Leonor Correia Guedes, Miguel Coelho, Mario M. Rosa, Joaquim J. Ferreira, Joana D. Amaral, Cecilia M. P. Rodrigues
Summary: The study reveals a protective role of miR-335 in experimental models of Parkinson's disease, showing its ability to combat inflammation and neurodegenerative events.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Biochemistry & Molecular Biology
Dominika Natalia Wojewska, Arjan Kortholt
Summary: This review provides a comprehensive overview of the current state of the art, presenting recent developments and challenges in developing LRRK2 inhibitors, and discussing extensively the potential targeting strategies from the protein perspective. As currently there are three LRRK2-targeting agents in clinical trials, more developments are predicted in the upcoming years.
Review
Biochemistry & Molecular Biology
Ailyn Irvita Ravinther, Hemaniswarri Dewi Dewadas, Shi Ruo Tong, Chai Nien Foo, Yu-En Lin, Cheng-Ting Chien, Yang Mooi Lim
Summary: Parkinson's disease is a common neurodegenerative disease affecting the ageing population, and its prevalence has increased in recent years. Mutations in Leucine-rich-repeat-kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease, and aberrant LRRK2 kinase activity is also associated with idiopathic Parkinson's disease. This review aims to categorize and synthesize current information on LRRK2-linked Parkinson's disease and identify potential therapeutic targets.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Alexander Myasnikov, Hanwen Zhu, Patricia Hixson, Boer Xie, Kaiwen Yu, Aaron Pitre, Junmin Peng, Ji Sun
Summary: Mutations in LRRK2 are commonly associated with Parkinson's disease. This study provides insights into the physiological and pathological roles of LRRK2, and establishes a structural template for future therapeutic interventions in PD. The high-resolution structures of full-length human LRRK2 and COR-mediated LRRK2 dimers reveal key elements for rationalizing disease-causing mutations and potential targets for inhibitors.
Review
Biochemistry & Molecular Biology
Ahsan Usmani, Farbod Shavarebi, Annie Hiniker
Summary: Point mutations in LRRK2 are common causes of familial and apparent sporadic Parkinson's disease. LRRK2-driven PD is clinically indistinguishable from sporadic PD, making it a valuable genetic model. Recent research highlights LRRK2's functions in the endolysosomal system and regulation by Rab GTPases, as well as its interaction with the cytoskeleton for protein degradation and inhibitor therapies. Interactions between LRRK2 and other PD-driving genes may illuminate broader cellular pathways disrupted in PD.
MOLECULAR AND CELLULAR BIOLOGY
(2021)
News Item
Biochemistry & Molecular Biology
Surya K. De
Summary: This patent describes the use of novel pyrroloppyrimidine compounds as LRRK2 kinase inhibitors for the treatment or prevention of diseases associated with LRRK2 kinase activity, such as Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis (ALS).
CURRENT MEDICINAL CHEMISTRY
(2023)
Review
Environmental Sciences
Sachin Kumar, Tapan Behl, Aayush Sehgal, Sridevi Chigurupati, Sukhbir Singh, Vasudevan Mani, Maha Aldubayan, Ahmed Alhowail, Satvinder Kaur, Saurabh Bhatia, Ahmed Al-Harrasi, Vetriselvan Subramaniyan, Shivkanya Fuloria, Neeraj Kumar Fuloria, Mahendran Sekar, Mohamed M. Abdel Daim
Summary: Major breakthroughs in understanding the role of biology in Parkinson's disease (PD) have identified mitochondrial dysfunction and the enzyme leucine-rich repeat kinase 2 (LRRK2) as important factors in the pathogenesis of the disease. Inhibiting LRRK2 kinase activity shows promise in preventing endolysosomal dysfunction and neurodegeneration in PD, making LRRK2 inhibitors potentially useful therapeutic targets.
ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Suzanne R. Pfeffer
Summary: Rab GTPases are critical regulators of secretory and endocytic pathways. Mutations in LRRK2 kinase lead to Parkinson's disease, and Rab GTPases are important substrates of LRRK2. Phosphorylation of Rab proteins by LRRK2 influences effector selection and has significant consequences for cell pathophysiology.
Article
Biochemistry & Molecular Biology
Jun Ogata, Kentaro Hirao, Kenya Nishioka, Arisa Hayashida, Yuanzhe Li, Hiroyo Yoshino, Soichiro Shimizu, Nobutaka Hattori, Yuzuru Imai
Summary: A novel LRRK2 variant-p.G2294R located in the WD40 domain was detected in a patient with familial Parkinson's disease through targeted gene-panel screening. This variant was found to be highly destabilized at the protein level. Experimental results showed upregulated expression of the LRRK2 p.G2294R protein in the patient's peripheral blood lymphocytes, while macrophages differentiated from the same blood sample exhibited decreased levels of LRRK2 protein. Additionally, reduced phagocytic activity was observed in pathogenic yeasts and alpha-synuclein fibrils.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Chen Dong, Chandrashekhar Honrao, Leonardo O. Rodrigues, Josephine Wolf, Keri B. Sheehan, Matthew Surface, Roy N. Alcalay, Elizabeth M. O'Day
Summary: Parkinson's disease is a progressive neurodegenerative disease with motor and nonmotor function loss. This study identified metabolic markers of PD in plasma and developed a machine learning model for PD diagnosis with high accuracy. The findings provide insights for the development of diagnostic tools for PD.
Article
Biochemistry & Molecular Biology
Stefan Gaussmann, Mohanraj Gopalswamy, Hamed Kooshapur, Chen Zheng, Iris Antes, Eva Hambruch, Wolfgang Schliebs, Ralf Erdmann, Michael Sattler
Summary: The cycling import receptor PEX5 and its binding partner PEX14 play important roles in the peroxisomal import machinery. They recognize cargo proteins carrying a peroxisomal targeting signal type 1 (PTS1) and dock at the peroxisomal membrane. This study characterizes the recognition of (di)aromatic peptides motifs by PEX14 and identifies key features involved in the interaction. The findings provide a refined consensus motif for high affinity binding to PEX14 and suggest conservation of the (di)aromatic peptide recognition by PEX14 in other species.
BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Asmaa Oun, Emmy Hoeksema, Ahmed Soliman, Famke Brouwer, Fabiola Garcia-Reyes, Henderikus Pots, Marina Trombetta-Lima, Arjan Kortholt, Amalia M. Dolga
Summary: Dysfunction of the immune system and mitochondrial metabolism is associated with Parkinson's disease (PD) pathology. Mutations and increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) are linked to both idiopathic and familial PD. However, the function of LRRK2 in immune cells under inflammatory conditions is contradictory.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Nele Merret Hollmann, Pravin Kumar Ankush Jagtap, Johanna-Barbara Linse, Philip Ullmann, Marco Payr, Brice Murciano, Bernd Simon, Jochen S. Hub, Janosch Hennig
Summary: RNA binding proteins (RBPs) use multiple RNA binding domains (RBDs) to increase target specificity and affinity. However, the complexity of target recognition by multiple RBDs is not well understood. This study demonstrates how multiple RBDs in the multidomain RBP Unr orchestrate target specificity. Structural analysis reveals the interaction surfaces between Unr and the poly(A)-binding protein (pAbp), providing insights into their cooperative role in cellular processes.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Philipp Keil, Alexander Wulf, Nitin Kachariya, Samira Reuscher, Kristin Huhn, Ivan Silbern, Janine Altmuller, Mario Keller, Ralf Stehle, Kathi Zarnack, Michael Sattler, Henning Urlaub, Katja Straesser
Summary: RNA-binding proteins (RBPs) control RNA metabolism through protein-RNA and protein-protein interactions. In this study, we identified in vivo RNA crosslinks in nuclear mRNP components and functionally analyzed the Npl3 protein. Mutations in the RNA recognition motifs (RRMs) and linker region of Npl3 revealed distinct functions of different RNA-binding domains. Importantly, a linker mutation impaired mRNP assembly, revealing a previously unknown function of Npl3. This integrative analysis can be applied to study RBPs in other RNA metabolic processes.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Multidisciplinary Sciences
Liselot Dewachter, Aaron N. N. Brooks, Katherine Noon, Charlotte Cialek, Alia Clark-ElSayed, Thomas Schalck, Nandini Krishnamurthy, Wim Versees, Wim Vranken, Jan Michiels
Summary: Deep mutational scanning is a powerful method for investigating protein function and stability. In this study, the researchers perform deep mutational scanning on three essential E. coli proteins and study the effects of mutations in their original genomic context. They use over 17,000 protein variants to explore protein function and the importance of individual amino acids. The study also evaluates resistance development against antimicrobial compounds and identifies potential targets for drug development.
NATURE COMMUNICATIONS
(2023)
Correction
Multidisciplinary Sciences
Liselot Dewachter, Aaron N. Brooks, Katherine Noon, Charlotte Cialek, Alia Clark-ElSayed, Thomas Schalck, Nandini Krishnamurthy, Wim Versees, Wim Vranken, Jan Michiels
NATURE COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Joel Roca-Martinez, Hrishikesh Dhondge, Michael Sattler, Wim Vranken
Summary: This study analyzed the interactions between RNA recognition motif (RRM) and RNA sequences through computational analysis, and identified the main binding mode and relevant amino acids. A predictor called RRMScorer was developed to predict the binding between RRM and RNA based on their sequences. This tool can be used to identify new potential RNA targets and design mutants with modified RNA binding capabilities.
PLOS COMPUTATIONAL BIOLOGY
(2023)
Article
Pharmacology & Pharmacy
Enrica Zanuttigh, Kevork Derderian, Miriam A. Guera, Arie Geerlof, Ivano Di Meo, Chiara Cavestro, Stefan Hempfling, Stephanie Ortiz-Collazos, Mario Mauthe, Tomasz Kmiec, Eugenia Cammarota, Maria Carla Panzeri, Thomas Klopstock, Michael Sattler, Juliane Winkelmann, Ana C. Messias, Arcangela Iuso
Summary: "Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a neurodegenerative disorder caused by mutations in the C19orf12 gene. This study found that there were no consistent alterations in mitochondrial functions or cellular signaling in MPAN fibroblasts, but autophagy initiation was consistently impaired. Furthermore, several potential therapeutic compounds for MPAN were identified through screening autophagy modulators."
Article
Chemistry, Multidisciplinary
Kevin Van Holsbeeck, Baptiste Fischer, Simon Gonzalez, Charlene Gadais, Wim Versees, Jose C. Martins, Charlotte Martin, Alexandre Wohlkoenig, Jan Steyaert, Steven Ballet
Summary: RAS proteins play a crucial role in regulating intracellular signaling networks and mutations that stabilize their active state are associated with cancer development. The study investigated the potential of developing peptide mimetics to modulate RAS signaling by mimicking the complementarity-determining region 3 (CDR3) of the regulatory guanine nucleotide exchange factor (GEF) son of sevenless 1 (SOS1). Through optimization and conformational rigidification, CDR3 mimetics with half of the maximal activation potential of Nanobody14 (Nb14) were obtained, demonstrating the feasibility of modulating protein-protein interactions through structural mimicry of a paratope.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
Article
Chemistry, Physical
Nicola Calonaci, Mattia Bernetti, Alisha Jones, Michael Sattler, Giovanni Bussi
Summary: In this study, we used atomistic molecular dynamics simulations to investigate the binding of RNA with SHAPE reagents. We proposed and tested the hypothesis that cooperative effects can lead to concentration-dependent reactivity. Our simulations and analysis of experimental data support the idea that cooperative binding can indeed affect the reactivity of SHAPE experiments.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2023)
Article
Neurosciences
Adekunle T. Bademosi, Marianna Decet, Sabine Kuenen, Carles Calatayud, Jef Swerts, Sandra F. Gallego, Nils Schoovaerts, Spyridoula Karamanou, Nikolaos Louros, Ella Martin, Jean-Baptiste Sibarita, Katlijn Vints, Natalia V. Gounko, Frederic A. Meunier, Anastassios Economou, Wim Versees, Frederic Rousseau, Joost Schymkowitz, Sandra-F. Soukup, Patrik Verstreken
Summary: Neuronal activity-induced calcium influx is connected to synaptic autophagy and neuronal survival through Endophilin-A in a Parkinson disease-relevant fashion. Mutations in the disordered loop of Endophilin-A render it insensitive to neuronal stimulation, affecting protein dynamics and autophagosome formation. Balanced stimulation-induced autophagy is critical for dopaminergic neuron survival, and a variant in the human ENDOA1 disordered loop conferring risk to Parkinson disease also blocks nanodomain protein mobility and autophagy in vivo and in human-induced dopaminergic neurons.
Article
Biochemistry & Molecular Biology
Babette Deckers, Silke Vercauteren, Veerke De Kock, Charlotte Martin, Tamas Lazar, Pauline Herpels, Liselot Dewachter, Natalie Verstraeten, Eveline Peeters, Steven Ballet, Jan Michiels, Christian Galicia, Wim Versees
Summary: This study identifies the DNA-binding protein YbiB as an interactor of the bacterial protein ObgE. The study also reveals the binding site between the C-terminal domain of ObgE and the positively charged groove on the surface of YbiB. Additionally, ObgE competes with DNA for binding to YbiB, indicating its role in the cellular processes involving YbiB.
NUCLEIC ACIDS RESEARCH
(2023)
Review
Biochemistry & Molecular Biology
Xiaojuan Zhang, Arjan Kortholt
Summary: Mutations in the LRRK2 gene are associated with Parkinson's disease, and LRRK2 contains multiple domains including two enzymatic domains and three N-terminal domains. The mutations in LRRK2 are found in various domains and lead to changes in kinase and GTPase activities. The activation mechanism of LRRK2 involves intramolecular regulation, dimerization, and membrane recruitment.
Article
Multidisciplinary Sciences
Komal Soni, Pravin Kumar Ankush Jagtap, Santiago Martinez-Lumbreras, Sophie Bonnal, Arie Geerlof, Ralf Stehle, Bernd Simon, Juan Valcarcel, Michael Sattler
Summary: This study reveals the structural mechanism of RNA-binding protein RBM5, which cooperates through multiple RNA-binding domains to recognize specific target RNA sequences and regulate alternative splicing of genes implicated in cancer.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Marin Matic, Pasquale Miglionico, Manae Tatsumi, Asuka Inoue, Francesco Raimondi
Summary: Selective formation of GPCR-G protein complexes is crucial for regulating signal transduction. By using a data-driven approach, the authors demonstrate that the structures of experimental and predicted complex interfaces provide information on G protein binding preferences. GPCRs are key regulators of cell signaling, transducing extracellular stimuli into the cell through selective coupling to intracellular G proteins. The authors conduct a computational analysis to investigate the structural determinants of G protein coupling in experimental and predicted 3D GPCR-G protein complexes.
NATURE COMMUNICATIONS
(2023)