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
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)
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
Geriatrics & Gerontology
Deborah L. Harrington, Qian Shen, Vida Sadeghi, Mingxiong Huang, Irene Litvan, Xiangyu Wei, Roland R. Lee
Summary: The study found two aberrant connectivity patterns in Parkinson's disease (PD) patients, with one pattern showing a loss in frontal, parietal, and temporal connections related to semantic recollection, and another pattern involving functional reconfiguration with strengthened connections in PD patients compared to controls. These findings suggest that changes in regional connectivity during semantic recollection may play a role in early cognitive vulnerabilities in PD patients.
FRONTIERS IN AGING NEUROSCIENCE
(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.
Review
Biochemistry & Molecular Biology
Genta Ito, Naoko Utsunomiya-Tate
Summary: Leucine-rich repeat kinase 2 (LRRK2) is a protein kinase that phosphorylates and regulates Rab proteins. Genetic mutations in LRRK2 are implicated in both familial and sporadic Parkinson's disease (PD), but the mechanism is not well understood. PD patients with LRRK2 mutations show clinical symptoms similar to typical PD, but the pathological manifestations in their brains can vary greatly. Pathogenic mutations in LRRK2 affect its function and structure, which may contribute to the differences observed in patient pathology. This review summarizes the clinical and pathological manifestations caused by LRRK2 mutations, their impact on LRRK2's molecular function and structure, and their historical background, aiming to aid researchers in understanding LRRK2-associated PD pathogenesis.
Article
Clinical Neurology
Ulf Jensen-Kondering, Nils G. Margraf, Caroline Weiler, Walter Maetzler, Justina Dargvainiene, Kim Falk, Sarah Philippen, Thorsten Bartsch, Charlotte Flueh, Christoph Roecken, Bettina Moeller, Georg Royl, Alexander Neumann, Norbert Brueggemann, Benjamin Roeben, Claudia Schulte, Benjamin Bender, Daniela Berg, Gregor Kuhlenbaeumer
Summary: This study compared the clinical, radiological, and cerebrospinal fluid marker data of patients with CAA, MLH, AD, and healthy controls. The results showed that cSS was more common in CAA, and MLH with cSS was associated with ICH. The concentrations of cerebrospinal fluid markers differed among the groups.
INTERNATIONAL JOURNAL OF STROKE
(2023)
Article
Clinical Neurology
Bernd Leplow, Daniela Renftle, Mareike Thomas, Katja Michaelis, Susanne Solbrig, Walter Maetzler, Daniela Berg, Inga Liepelt-Scarfone
Summary: Impulse control disorders (ICD) frequently occur in Parkinson's disease (PD), not always as a direct consequence of medication. This study investigated premorbid personality traits and behavioral characteristics in non-demented PD patients with self-reported symptoms of ICD (PD-srICD). It was found that patients with PD-srICD had similarities with substance use disorder patients, and thorough psychological diagnostics are recommended.
JOURNAL OF NEURAL TRANSMISSION
(2023)
Article
Neurosciences
Gabrielle Todd, Caroline D. Rae, Janet L. Taylor, Nigel C. Rogasch, Jane E. Butler, Michael Hayes, Robert A. Wilcox, Simon C. Gandevia, Karl Aoun, Adrian Esterman, Simon J. G. Lewis, Julie M. Hall, Elie Matar, Jana Godau, Daniela Berg, Christian Plewnia, Anna-Katharina Von Thaler, Clarence Chiang, Kay L. Double
Summary: Research has found that increased thickness of the substantia nigra in healthy older adults may be associated with changes in excitability of motor cortical circuitry. This finding has important implications for understanding brain changes in healthy older adults at risk of Parkinson's disease.
JOURNAL OF NEUROSCIENCE RESEARCH
(2023)
Letter
Clinical Neurology
Gunther Deuschl, Angelo Antonini, Joao Costa, Katarzyna Smilowska, Daniela Berg, Jean-Christophe Corvol, Giovanni Fabbrini, Joaquim Ferreira, Tom Foltynie, Pablo Mir, Anette Schrag, Klaus Seppi, Pille Taba, Evzen Ruzicka, Marianna Selikhova, Nicholas Henschke, Gemma Villanueva, Elena Moro
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
Thomas Gasser
Summary: After years of research and setbacks, gene therapies have achieved undeniable success by directly modifying genetic information on the DNA or RNA level. Both ex vivo strategies, manipulating patient cells outside the body, and in vivo approaches have been successful. In addition to gene supplementation, the use of the CRISPR-Cas9 system for altering nuclear DNA sequences and interfering with the transcriptional process on the RNA level can also be considered as gene therapies in a broad sense.
FORTSCHRITTE DER NEUROLOGIE PSYCHIATRIE
(2023)
Review
Clinical Neurology
Ullrich Wuellner, Per Borghammer, Chi-un Choe, Ilona Csoti, Bjorn Falkenburger, Thomas Gasser, Paul Lingor, Peter Riederer
Summary: The heterogeneity of Parkinson's disease presents challenges for future research and therapeutic design. Various pathophysiological concepts and mechanisms, including alpha-synuclein misfolding, oxidative stress, and microbial agents, may contribute to the development of PD. The unresolved heterogeneity of PD has hindered previous clinical trials, highlighting the need for personalized therapeutic approaches.
JOURNAL OF NEURAL TRANSMISSION
(2023)
Review
Clinical Neurology
Thomas Gasser
Summary: The identification of disease-causing mutations or strong risk factors for Parkinson's disease in specific genes has led to a better understanding of disease pathogenesis. Many gene and mutation-specific targeted disease-modifying treatments are being developed and studied. Therefore, it is important to raise awareness and offer genetic testing to patients considering innovative trials.
JOURNAL OF NEURAL TRANSMISSION
(2023)
Article
Clinical Neurology
Pierre-Emmanuel Sugier, Elise A. Lucotte, Cloe Domenighetti, Matthew H. Law, Mark M. Iles, Kevin Brown, Christopher Amos, James D. McKay, Rayjean J. Hung, Mojgan Karimi, Delphine Bacq-Daian, Anne Boland-Auge, Robert Olaso, Jean-francois Deleuze, Fabienne Lesueur, Evgenia Ostroumova, Ausrele Kesminiene, Florent de Vathaire, Pascal Guenel, Ashwin Ashok Kumar Sreelatha, Claudia Schulte, Sandeep Grover, Patrick May, Dheeraj R. Bobbili, Milena Radivojkov-Blagojevic, Peter Lichtner, Andrew B. Singleton, Dena G. Hernandez, Connor Edsall, George D. Mellick, Alexander Zimprich, Walter Pirker, Ekaterina Rogaeva, Anthony E. Lang, Sulev Koks, Pille Taba, Suzanne Lesage, Alexis Brice, Jean-Christophe Corvol, Marie-Christine Chartier-Harlin, Eugenie Mutez, Kathrin Brockmann, Angela B. Deutschlaender, Georges M. Hadjigeorgiou, Efthimios Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Hirotaka Matsuo, Akiyoshi Nakayama, Nobutaka Hattori, Kenya Nishioka, Sun Ju Chung, Yun Joong Kim, Pierre Kolber, Bart P. C. van de Warrenburg, Bastiaan R. Bloem, Jan Aasly, Mathias Toft, Lasse Pihlstrom, Leonor Correia Guedes, Joaquim J. Ferreira, Soraya Bardien, Jonathan Carr, Eduardo Tolosa, Mario Ezquerra, Pau Pastor, Monica Diez-Fairen, Karin Wirdefeldt, Nancy Pedersen, Caroline Ran, Andrea C. Belin, Andreas Puschmann, Emil Ygland Roedstroem, Carl E. Clarke, Karen E. Morrison, Manuela Tan, Dimitri Krainc, Lena F. Burbulla, Matt J. Farrer, Rejko Kruger, Thomas Gasser, Manu Sharma, Therese Truong, Alexis Elbaz
Summary: By using genome-wide association studies, this study found that Parkinson's disease (PD) is genetically correlated with melanoma and prostate cancer, while it is inversely correlated with ovarian cancer. These findings suggest that pleiotropic genes contribute to the association between PD and specific cancers.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Anastasia Kuzkina, Celine Panzer, Aline Seger, Daniela Schmitt, Jonas Roessle, Sebastian R. Schreglmann, Henrike Knacke, Elena Salabasidou, Antonia Kohl, Elisabeth Sittig, Michael Barbe, Daniela Berg, Jens Volkmann, Claudia Sommer, Wolfgang H. Oertel, Eva Schaeffer, Michael Sommerauer, Annette Janzen, Kathrin Doppler
Summary: The study assessed the use of RT-QuIC method to detect alpha-synuclein aggregation in skin biopsy samples of iRBD patients. It was found that 97.4% of iRBD patients, 87.2% of PD patients, and 13% of controls showed aggregation of alpha-synuclein. RT-QuIC was more sensitive but less specific compared to immunohistochemistry.
MOVEMENT DISORDERS
(2023)
Letter
Clinical Neurology
Guenther Deuschl, Angelo Antonini, Joao Costa, Katarzyna Smilowska, Daniela Berg, Jean-Christophe Corvol, Giovanni Fabbrini, Joaquim Ferreira, Tom Foltynie, Pablo Mir, Anette Schrag, Klaus Seppi, Pille Taba, Evzen Ruzicka, Marianna Selikhova, Nicholas Henschke, Gemma Villanueva, Elena Moro
MOVEMENT DISORDERS
(2023)
Article
Multidisciplinary Sciences
Meemansa Sood, Ulrike Suenkel, Anna-Katharina von Thaler, Helena U. U. Zacharias, Kathrin Brockmann, Gerhard W. Eschweiler, Walter Maetzler, Daniela Berg, Holger Froehlich, Sebastian Heinzel
Summary: Parkinson's disease (PD) has a long prodromal phase with many markers indicating an increased risk prior to clinical diagnosis. Current prediction models lack consideration of interdependencies between predictors and differentiation by subtypes, and may be limited by confounding factors and restricted data access. Using AI and a Bayesian network, we analyzed data from 1178 healthy individuals and 24 incident PD cases to quantify marker interdependencies and generate synthetic profiles. We identified robust interdependencies and demonstrated the usefulness of AI in modeling and understanding PD markers.
Article
Clinical Neurology
Stephan Greten, Florian Wegner, Ida Jensen, Lea Krey, Sophia Rogozinski, Meret Fehring, Johanne Heine, Johanna Doll-Lee, Monika Poetter-Nerger, Molly Zeitzschel, Keno Hagena, David J. Pedrosa, Carsten Eggers, Katrin Buerk, Claudia Trenkwalder, Inga Claus, Tobias Warnecke, Patrick Suess, Juergen Winkler, Doreen Gruber, Florin Gandor, Daniela Berg, Steffen Paschen, Joseph Classen, Elmar H. Pinkhardt, Jan Kassubek, Wolfgang H. Jost, Lars Toenges, Andrea A. Kuehn, Johannes Schwarz, Oliver Peters, Eman Dashti, Josef Priller, Eike J. Spruth, Patricia Krause, Annika Spottke, Anja Schneider, Aline Beyle, Okka Kimmich, Markus Donix, Robert Haussmann, Moritz Brandt, Elisabeth Dinter, Jens Wiltfang, Bjoern H. Schott, Inga Zerr, Mathias Baehr, Katharina Buerger, Daniel Janowitz, Robert Perneczky, Boris-Stephan Rauchmann, Endy Weidinger, Johannes Levin, Sabrina Katzdobler, Emrah Duezel, Wenzel Glanz, Stefan Teipel, Ingo Kilimann, Johannes Prudlo, Thomas Gasser, Kathrin Brockmann, Daniel C. Hoffmann, Thomas Klockgether, Olaf Krause, Johannes Heck, Guenter U. Hoeglinger, Martin Klietz
Summary: This study explored the pattern of comorbidities and co-medication in PSP patients. It found that PSP patients have a higher prevalence of cardiovascular diseases and diabetes, and they receive a greater number of drugs, leading to a higher prevalence of polypharmacy.
JOURNAL OF NEUROLOGY
(2023)
Article
Clinical Neurology
Nir Giladi, Roy N. Alcalay, Gary Cutter, Thomas Gasser, Tanya Gurevich, Guenter U. Hoeglinger, Kenneth Marek, Claudio Pacchetti, Anthony H. Schapira, Clemens R. Scherzer, Tanya Simuni, Pascal Minini, S. Pablo Sardi, M. Judith Peterschmitt
Summary: The safety, efficacy, and target engagement of venglustat in early-stage Parkinson's disease patients with GBA1 variants were assessed. The study showed that venglustat had a satisfactory safety profile but did not show beneficial treatment effect compared with placebo. These findings suggest that glucosylceramide synthase inhibition with venglustat may not be a viable therapeutic approach for GBA1-associated Parkinson's disease.
Review
Clinical Neurology
Isaac Bul Deng, Jordan Follett, Mengfei Bu, Matthew J. Farrer
Summary: Recent studies have shown that pathogenic variants in DNAJC12 can cause various diseases, including mild hyperphenylalaninemia, infantile dystonia, young-onset parkinsonism, developmental delay and cognitive deficits. DNAJC12 has been included in newborn screening, particularly in Spain, emphasizing the importance of genetic diagnosis and early intervention. However, many practitioners may not be aware of these advances, and molecular testing for DNAJC12 is yet to be conducted for many patients, especially adults. This review provides a summary of genotype-phenotype relationships and treatment approaches for patients with pathogenic variants in DNAJC12, as well as an overview of the protein's structure, known genetic variants, domains, binding partners, and its role in monoamine synthesis, disease etiology, and pathogenesis.
MOVEMENT DISORDERS
(2023)
Letter
Clinical Neurology
Christos Koros, Kathrin Brockmann, Athina-Maria Simitsi, Anastasia Bougea, Hui Liu, Ann-Kathrin Hauser, Claudia Schulte, Stefanie Lerche, Ioanna Pachi, Nikolaos Papagiannakis, Roubina Antonelou, Athina Zahou, Isabel Wurster, Efthymia Efthymiopoulou, Ion Beratis, Matina Maniati, Marina Moraitou, Helen Michelakakis, Georgios Paraskevas, Sokratis G. Papageorgiou, Constantin Potagas, Dimitra Papadimitriou, Maria Bozi, Maria Stamelou, Thomas Gasser, Leonidas Stefanis
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Jun-Pyo Hong, Hanim Kwon, Euyhyun Park, Sun-Uk Lee, Chan-Nyoung Lee, Byung-Jo Kim, Ji-Soo Kim, Kun-Woo Park
Summary: In patients with mild-to-moderate PD, vestibular function assessed by video head-impulse tests appears relatively preserved and has minimal impact on the risk of falls. Risk of postural instability is associated with the severity of clinical symptoms in PD.
PARKINSONISM & RELATED DISORDERS
(2024)
Article
Clinical Neurology
Yaqin Xiang, XiuRong Huang, Qian Xu, Zhenhua Liu, Yase Chen, Qiying Sun, Junling Wang, Hong Jiang, Lu Shen, Xinxiang Yan, Beisha Tang, Jifeng Guo
Summary: Using the novel data-driven method DEBM, this study determined the sequence of several common biomarker changes in Parkinson's disease (PD). The left putamen was found to be the earliest biomarker to become abnormal, followed by the right putamen, CSF alpha-synuclein, right caudate, left caudate, and serum NfL. The estimated disease stages showed significant differences between PD and healthy controls, and achieved a high accuracy for distinguishing PD from HC.
PARKINSONISM & RELATED DISORDERS
(2024)
Article
Clinical Neurology
Yan Li, David J. McLernon, Carl E. Counsell, Angus D. Macleod
Summary: This study aimed to investigate the incidence and risk factors for institutionalisation in Parkinson's disease (PD) and atypical parkinsonism (AP). The study found that institutionalisation was more frequent in AP compared to PD and controls. Age, poorer cognition, and more-severe parkinsonian impairment were independent predictors of institutionalisation.
PARKINSONISM & RELATED DISORDERS
(2024)