Article
Multidisciplinary Sciences
Giuliana G. Repetti, Yuri Kim, Alexandre C. Pereira, Jodie Ingles, Mark W. Russell, Neal K. Lakdawala, Carolyn Y. Ho, Sharlene Day, Christopher Semsarian, Barbara McDonough, Steven R. DePalma, Daniel Quiat, Eric M. Green, Christine E. Seidman, J. G. Seidman
Summary: The clinical expression of hypertrophic cardiomyopathy (HCM) is influenced by background genetic variation and environmental factors. A study of 11 pairs of monozygotic HCM twins showed discordant cardiac morphology even among twins with the same pathogenic variant, indicating a significant role for epigenetics and environment in HCM disease progression. Whole genome sequencing analysis did not reveal notable somatic genetic variants to explain the clinical differences in the twins.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Clinical Neurology
Carlotta Bolliri, Alessandra Fontana, Emanuele Cereda, Michela Barichella, Roberto Cilia, Valentina Ferri, Serena Caronni, Daniela Calandrella, Lorenzo Morelli, Gianni Pezzoli
Summary: Differences in gut microbiota between Parkinson's disease patients and controls may be influenced by various confounding factors. Using monozygotic twins, this study controlled for these factors and found minimal differences in bacterial taxa abundance and predicted metabolic pathways. Further research is needed to understand the role of gut microbiota in the pathogenesis of Parkinson's disease.
ANNALS OF NEUROLOGY
(2022)
Article
Psychiatry
C. Iranzo-Tatay, D. Hervas-Marin, L. M. Rojo-Bofill, D. Garcia, F. J. Vaz-Leal, I Calabria, L. Beato-Fernandez, S. Oltra, J. Sandoval, L. Rojo-Moreno
Summary: This study focuses on the epigenomic landscapes in twin samples discordant for Anorexia nervosa (AN), aiming to find evidence for the role of epigenetic variations in AN's etiology. The study reveals genetic links between AN and metabolic traits, as well as psychiatric comorbidity.
TRANSLATIONAL PSYCHIATRY
(2022)
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.
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
Neurosciences
Emily M. Rocha, Matthew T. Keeney, Roberto Di Maio, Briana R. De Miranda, J. Timothy Greenamyre
Summary: The etiology of idiopathic Parkinson's disease involves multiple factors, including genetics and environmental exposures. LRRK2 plays an important role in iPD, regardless of mutations, by influencing kinase activation and substrate phosphorylation, which contribute to the pathogenesis.
TRENDS IN NEUROSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Leah G. Helton, Ahmed Soliman, Felix von Zweydorf, Michalis Kentros, Jascha T. Manschwetus, Scotty Hall, Bernd Gilsbach, Franz Y. Ho, Panagiotis S. Athanasopoulos, Ranjan K. Singh, Timothy J. LeClair, Wim Versees, Francesco Raimondi, Friedrich W. Herberg, Christian Johannes Gloeckner, Hardy Rideout, Arjan Kortholt, Eileen J. Kennedy
Summary: Dimerization of LRRK2 can be inhibited by specific constrained peptides, leading to decreased kinase activity, reduced ROS production, and inhibition of PD-related apoptosis in primary cortical neurons. Unlike other inhibitors, these peptides do not affect the cellular localization of LRRK2.
ACS CHEMICAL BIOLOGY
(2021)
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)
Review
Clinical Neurology
Yuri L. Sosero, Ziv Gan-Or
Summary: LRRK2 variants are associated with both familial and sporadic PD. LRRK2-PD presents with benign clinical features and variable pathology, including inconsistent presence of Lewy bodies and significant Alzheimer's disease pathology. The mechanisms of LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested. Understanding the role and function of LRRK2 in PD is important as novel therapies targeting LRRK2 are being developed.
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
(2023)
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.
Article
Clinical Neurology
Dongbing Lai, Babak Alipanahi, Pierre Fontanillas, Tae-Hwi Schwantes-An, Jan Aasly, Roy N. Alcalay, Gary W. Beecham, Daniela Berg, Susan Bressman, Alexis Brice, Kathrin Brockman, Lorraine Clark, Mark Cookson, Sayantan Das, Vivianna Van Deerlin, Jordan Follett, Matthew J. Farrer, Joanne Trinh, Thomas Gasser, Stefano Goldwurm, Emil Gustavsson, Christine Klein, Anthony E. Lang, J. William Langston, Jeanne Latourelle, Timothy Lynch, Karen Marder, Connie Marras, Eden R. Martin, Cory Y. McLean, Helen Mejia-Santana, Eric Molho, Richard H. Myers, Karen Nuytemans, Laurie Ozelius, Haydeh Payami, Deborah Raymond, Ekaterina Rogaeva, Michael P. Rogers, Owen A. Ross, Ali Samii, Rachel Saunders-Pullman, Birgitt Schule, Claudia Schulte, William K. Scott, Caroline Tanner, Eduardo Tolosa, James E. Tomkins, Dolores Vilas, John Q. Trojanowski, Ryan Uitti, Jeffery M. Vance, Naomi P. Visanji, Zbigniew K. Wszolek, Cyrus P. Zabetian, Anat Mirelman, Nir Giladi, Avi Orr Urtreger, Paul Cannon, Brian Fiske, Tatiana Foroud
Summary: This study identified a variant in the intronic region of CORO1C that may modify the penetrance of LRRK2 mutations, and common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.
ANNALS OF NEUROLOGY
(2021)
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
Obstetrics & Gynecology
Sophie G. Groene, Lisette Jansen, Ratna N. G. B. Tan, Sylke J. Steggerda, Monique C. Haak, Arno A. W. Roest, Enrico Lopriore, Jeanine M. M. van Klink
Summary: This study investigated the psychosocial development of monochorionic twins born after selective fetal growth restriction (sFGR) and found that they had a higher level of attachment insecurity and school problems. Smaller twins were more prone to negative emotions and internalizing behaviors compared to larger twins.
EARLY HUMAN DEVELOPMENT
(2022)
Review
Neurosciences
Shirley Yin-Yu Pang, Rachel Cheuk Nam Lo, Philip Wing-Lok Ho, Hui-Fang Liu, Eunice Eun Seo Chang, Chi-Ting Leung, Yasine Malki, Zoe Yuen-Kiu Choi, Wing Yan Wong, Michelle Hiu-Wai Kung, David Boyer Ramsden, Shu-Leong Ho
Summary: Mutations in LRRK2 and GBA are the most common genetic causes of Parkinson's disease, affecting the autophagic-lysosomal pathway. These genes influence each other, leading to autophagic defects, alpha-synuclein accumulation, and worsened clinical symptoms. Inhibitors of LRRK2 kinase and activators of GCase show promise in pre-clinical models, but their efficacy in idiopathic Parkinson's disease remains uncertain.
TRANSLATIONAL NEURODEGENERATION
(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.
