Article
Clinical Neurology
Dongling Zhang, Liche Zhou, Yuting Shi, Jun Liu, Hongjiang Wei, Qiqi Tong, Hongjian He, Tao Wu
Summary: The study found that the free water (FW) values in the posterior substantia nigra (pSN) were significantly elevated and continued to increase in asymptomatic LRRK2 G2019S mutation carriers. There was also a negative correlation between FW changes in the left pSN and striatal binding ratio (SBR) changes in the left putamen.
MOVEMENT DISORDERS
(2023)
Article
Biochemistry & Molecular Biology
Noemie Cresto, Camille Gardier, Marie-Claude Gaillard, Francesco Gubinelli, Pauline Roost, Daniela Molina, Charlene Josephine, Noelle Dufour, Gwenaelle Auregan, Martine Guillermier, Sueva Bernier, Caroline Jan, Pauline Gipchtein, Philippe Hantraye, Marie-Christine Chartier-Harlin, Gilles Bonvento, Nadja Van Camp, Jean-Marc Taymans, Karine Cambon, Geraldine Liot, Alexis-Pierre Bemelmans, Emmanuel Brouillet
Summary: The C-terminal domain of mutated LRRK2 was shown to induce neurodegeneration of dopaminergic neurons independently of its N-terminal domains and through cell-autonomous mechanisms. Mutated alpha-syn toxicity can be enhanced by the C-terminal domain of LRRK2 through cell-autonomous mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Clinical Neurology
S. Schootemeijer, D. Coker, J. F. Shelton, E. Chanoff, H. M. Rowbotham, S. K. L. Darweesh, B. R. Bloem, P. Cannon, N. M. de Vries
Summary: This study investigates the awareness, barriers, and motivators to exercise among individuals with and without manifest Parkinson's disease (PD) who carry the LRRK2 G2019S mutation. The results show that a high percentage of individuals are aware of the relationship between exercise and PD, but there are differences in barriers and motivators between those with and without manifest PD. Lack of motivation is the top barrier for nonmanifest PD individuals, while injury/disability is the most common barrier for manifest PD individuals. Improving body functioning is the primary motivator for both groups.
PARKINSONISM & RELATED DISORDERS
(2023)
Review
Pharmacology & Pharmacy
Jillian H. Kluss, Patrick A. Lewis, Elisa Greggio
Summary: This review provides updates on the current status of drugs and technologies targeting LRRK2 in the treatment of PD, evaluating their efficacy and overall safety in animal models and humans.
EXPERT OPINION ON THERAPEUTIC TARGETS
(2022)
Article
Cell Biology
Barbara Calamini, Nathalie Geyer, Nathalie Huss-Braun, Annie Bernhardt, Veronique Harsany, Pierrick Rival, May Cindhuchao, Dietmar Hoffmann, Sabine Gratzer
Summary: Parkinson's disease is a fatal neurodegenerative disorder primarily caused by the degeneration of dopaminergic neurons, with mutations in LRRK2 being a common genetic cause. Researchers have developed a PD model using LUHMES cell-derived dopaminergic neurons overexpressing G2019S LRRK2, which can help study G2019S LRRK2-mediated dopaminergic dysfunction and screen for novel PD therapeutics.
DISEASE MODELS & MECHANISMS
(2021)
Article
Clinical Neurology
Alicia Garrido, Enrique Santamaria, Joaquin Fernandez-Irigoyen, Marta Soto, Cristina Simonet, Manel Fernandez, Donina Obiang, Eduardo Tolosa, Maria-Jose Marti, Shalini Padmanabhan, Cristina Malagelada, Mario Ezquerra, Ruben Fernandez-Santiago
Summary: This study investigated protein and phospho-protein changes related to the G2019S mutant LRRK2 and identified specific phospho-protein changes associated with disease status. The findings can help distinguish different patient groups.
MOVEMENT DISORDERS
(2022)
Article
Multidisciplinary Sciences
Yuan Liu, Congqing Hao, Wei Zhang, Yuzhou Liu, Sen Guo, Ran Li, Meng Peng, Yawei Xu, Xiaoxin Pei, Haibo Yang, Yintao Zhao
Summary: In this study, it was found that LRRK2 deficiency protected the heart against cardiac remodeling induced by pressure overload by regulating autophagy levels.
JOURNAL OF ADVANCED RESEARCH
(2022)
Article
Cell Biology
Christiane Zhu, Susanne Herbst, Patrick A. Lewis
Summary: LRRK2 is a multidomain protein involved in regulating signaling pathways and cellular processes. It is associated with diseases such as Parkinson's disease. Research on LRRK2 aims to uncover its mechanisms and find new therapies.
JOURNAL OF CELL SCIENCE
(2023)
Review
Biochemistry & Molecular Biology
Ruiwei Cao, Caiping Chen, Jing Wen, Weihe Zhao, Chaojun Zhang, Longhui Sun, Liyan Yuan, Chunlei Wu, Lei Shan, Meiyang Xi, Haopeng Sun
Summary: This review provides an overview of Parkinson's disease (PD) and LRRK2, highlighting the structure, pathogenic mutations, and mechanism of LRRK2. It summarizes the development of LRRK2 inhibitors in preclinical and clinical studies. The review aims to provide insights into targeting LRRK2 for PD intervention in the future.
BIOORGANIC CHEMISTRY
(2023)
Article
Environmental Sciences
Jin-Ping Wang, Ji-Ping Yan, Rui-Ling Xiao, Rong-Shan Li
Summary: LRRK2 plays a protective role in acute kidney injury by enhancing podocyte autophagy and cell viability.
ENVIRONMENTAL TOXICOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Taghreed A. Majrashi, Shadma Wahab, Mohammad Ali Abdullah Almoyad, Ali Gaithan Alkhathami, Mohammad Y. Alshahrani
Summary: This study identified a potential LRRK2 inhibitor from natural compounds through computational virtual screening and molecular dynamics simulations. The compound showed significant affinity and specificity towards the LRRK2 binding pocket, making it a promising candidate for the treatment of PD and other neurodegenerative disorders.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2023)
Article
Chemistry, Medicinal
Robert K. Lesniak, R. Jeremy Nichols, Marcus Schonemann, Jing Zhao, Chandresh R. Gajera, William L. Fitch, Grace Lam, Khanh C. Nguyen, Mark Smith, Thomas J. Montine
Summary: This study reports the development of a selective LRRK2 inhibitor for the G2019S mutation, which can enter the brain by crossing the blood-brain barrier. These compounds provide a starting point for the development of brain-penetrant selective inhibitors targeting the G2019S mutation.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Genta Ito, Taisuke Tomita, Naoko Utsunomiya-Tate
Summary: In this study, it was found that the abnormal increase in phosphorylation of Rab12 by LRRK2 is attributed to the structural differences caused by the bound nucleotide, and that Rab12 phosphorylation inhibits its activation. The research also showed that Rab12 in its GDP-bound form is more susceptible to heat-induced denaturation and has a lower thermal stability compared to its GTP-bound form. These findings provide insights into unraveling the mechanism behind the abnormal increase in Rab12 phosphorylation.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2023)
Article
Neurosciences
Alison Fellgett, C. Adam Middleton, Jack Munns, Chris Ugbode, David Jaciuch, Laurence G. Wilson, Sangeeta Chawla, Christopher J. H. Elliott
Summary: In Drosophila dopaminergic neurons, Rab10 is involved in some, but not all, LRRK2-induced behavioral deficits. Therefore, variations in Rab expression may contribute to susceptibility of different dopaminergic nuclei to neurodegeneration seen in people with Parkinson's disease.
JOURNAL OF PARKINSONS DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Sara Kim, Jeonghyang Park, Byeong Wook Jeon, Geonhee Hwang, Na Young Kang, Yeim We, Won-Young Park, Eunkyoo Oh, Jungmook Kim
Summary: This study presents an engineered rapamycin-inducible dimerization receptor system that can trigger LRR-RK signaling independent of ligands or endogenous receptors. By using this system, the authors demonstrated that rapamycin-mediated association can activate downstream brassinosteroid signaling and immune responses, while also revealing the potential functions and differential activities of some LRR-RKs in immune signaling.
Article
Gastroenterology & Hepatology
Marlene Schwarzfischer, Anna Niechcial, Kristina Handler, Yasser Morsy, Marcin Wawrzyniak, Andrea S. Laimbacher, Kirstin Atrott, Roberto Manzini, Katharina Baebler, Larissa Hering, Egle Katkeviciute, Janine Hafliger, Silvia Lang, Maja E. Keller, Jerome Woodtli, Lisa Eisenbeiss, Thomas Kraemer, Elisabeth M. Schraner, Mahesa Wiesendanger, Sebastian Zeissig, Gerhard Rogler, Andreas E. Moor, Michael Scharl, Marianne R. Spalinger
Summary: This study investigates the interaction between the PTPN22 gene variation and food-grade titanium dioxide nanoparticles in the pathogenesis of inflammatory bowel disease (IBD). The results show that the ingestion of titanium dioxide nanoparticles makes mice carrying the PTPN22 variation susceptible to IBD and triggers severe intestinal inflammation. This demonstrates that environmental factors can interact with genetic risk variants and reverse a protective mechanism into a disease-promoting effect.
Article
Biochemistry & Molecular Biology
Laura J. Smith, Magdalena M. Bolsinger, Kai-Yin Chau, Matthew E. Gegg, Anthony H. Schapira
Summary: Sequence variants or mutations in the GBA gene are the most important risk factor for Parkinson's disease. This study characterizes the effects of the E326K variant in human cells and finds that it behaves differently compared to other common GBA mutations. However, lipid imbalance and alpha-synuclein pathology are still observed.
HUMAN MOLECULAR GENETICS
(2023)
Article
Gastroenterology & Hepatology
Joana Torres, Maria Chaparro, Mette Julsgaard, Konstantinos Katsanos, Zuzana Zelinkova, Manasi Agrawal, Sandro Ardizzone, Marjo Campmans-Kuijpers, Gabriele Dragoni, Marc Ferrante, Gionata Fiorino, Emma Flanagan, Catarina Frias Gomes, Ailsa Hart, Charlotte Rose Hedin, Pascal Juillerat, Annemarie Mulders, Par Myrelid, Aoibhlinn O'Toole, Pauline Riviere, Michael Scharl, Christian Philipp Selinger, Elena Sonnenberg, Murat Toruner, Jantien Wieringa, C. Janneke Van der Woude
JOURNAL OF CROHNS & COLITIS
(2023)
Article
Clinical Neurology
Kimberley J. Billingsley, Jinhui Ding, Pilar Alvarez Jerez, Anastasia Illarionova, Kristin Levine, Francis P. Grenn, Mary B. Makarious, Anni Moore, Daniel Vitale, Xylena Reed, Dena Hernandez, Ali Torkamani, Mina Ryten, John Hardy, Ruth W. Chia, Sonja J. Scholz, Bryan L. Traynor, Clifton J. Dalgard, Debra Ehrlich, Toshiko Tanaka, Luigi G. Ferrucci, Thomas E. Beach, Geidy P. Serrano, John J. Quinn, Vivien Bubb, Ryan L. Collins, Xuefang Zhao, Mark Walker, Emma Pierce-Hoffman, Harrison E. Brand, Michael Talkowski, Bradford Casey, Mark R. Cookson, Androo A. Markham, Mike Nalls, Medhat Mahmoud, Fritz J. Sedlazeck, Cornelis Blauwendraat, J. Raphael B. Gibbs, Andrew Singleton
Summary: By studying the genetic factors of Parkinson's disease, three structural variants associated with the risk of the disease have been discovered. This is the most comprehensive study to date of the contribution of structural variants to the genetic risk of Parkinson's disease.
ANNALS OF NEUROLOGY
(2023)
Article
Clinical Neurology
Zhongbo Chen, Arianna Tucci, Valentina Cipriani, Emil K. Gustavsson, Kristina Ibanez, Regina H. Reynolds, David Zhang, Letizia Vestito, Alejandro Cisterna Garcia, Siddharth Sethi, Jonathan W. Brenton, Sonia Garcia-Ruiz, Aine Fairbrother-Browne, Ana-Luisa Gil-Martinez, Nick Wood, John A. Hardy, Damian Smedley, Henry Houlden, Juan Botia, Mina Ryten
Summary: Using a systems biology approach, Chen et al. found that genes associated with adult- and child-onset ataxia share common characteristics, including a high density of short tandem repeats. Removing the age-of-onset partition and screening for repeat expansions could improve the diagnosis of hereditary ataxia.
Article
Clinical Neurology
Raquel Real, Alejandro Martinez-Carrasco, Regina H. Reynolds, Michael A. Lawton, Manuela M. X. Tan, Maryam Shoai, Jean-Christophe Corvol, Mina Ryten, Catherine Bresner, Leon Hubbard, Alexis Brice, Suzanne Lesage, Johann Faouzi, Alexis Elbaz, Fanny Artaud, Nigel Williams, Michele T. M. Hu, Yoav Ben-Shlomo, Donald G. Grosset, John Hardy, Huw R. Morris
Summary: Researchers performed a genome-wide survival study on almost 4000 Parkinson's disease patients and identified new genetic loci associated with faster progression to Parkinson's disease dementia, including the LRP1B receptor. Parkinson's disease is a common neurodegenerative disorder, and cognitive impairment and dementia are important features in the later stages of the disease. The genetic basis for the heterogeneity in cognitive decline among Parkinson's disease patients is not fully understood.
Article
Biology
Thomas H. Julian, Johnathan Cooper-Knock, Stuart MacGregor, Hui Guo, Tariq Aslam, Eleanor Sanderson, Graeme C. M. Black, Panagiotis Sergouniotis, Lois E. H. Smith
Summary: Age-related macular degeneration (AMD) is a leading cause of blindness, and this study aims to identify causal factors and potential therapeutic targets for AMD through a phenome-wide Mendelian randomisation (MR) study. The results of this study support several putative causal factors for AMD and provide avenues for future translational research.
Editorial Material
Clinical Neurology
John Hardy, Catherine Mummery
Review
Clinical Neurology
Tiago F. Outeiro, Roy N. Alcalay, Angelo Antonini, Johannes Attems, Vincenzo Bonifati, Francisco Cardoso, Marie-Francoise Chesselet, John Hardy, Graziella Madeo, Ian McKeith, Brit Mollenhauer, Darren J. Moore, Olivier Rascol, Michael G. Schlossmacher, Hermona Soreq, Leonidas Stefanis, Joaquim J. Ferreira
Summary: Parkinson's disease is a complex syndrome with inconsistent definitions in various domains. To make breakthroughs in treatment, it is important to integrate the diverse disciplines and define the endophenotypes of typical PD accurately.
MOVEMENT DISORDERS
(2023)
Correction
Multidisciplinary Sciences
Gaolian Xu, Hao Yang, Jiani Qiu, Julien Reboud, Linqing Zhen, Wei Ren, Hong Xu, Jonathan M. Cooper, Hongchen Gu
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Gaolian Xu, Hao Yang, Jiani Qiu, Julien Reboud, Linqing Zhen, Wei Ren, Hong Xu, Jonathan M. M. Cooper, Hongchen Gu
Summary: The authors propose a method called STEM-PCR for rapid and facile detection of specific nucleic acid modifications. This method utilizes a simple and widely accessible PCR-based workflow, and exhibits sensitivity 20 times greater than current gold-standard techniques by using a bisulfite-free process. They successfully demonstrate the clinical applicability of this method by detecting methylation of SEPTIN9 and SFRP2 genes, which are key biomarkers in tumor prognosis and diagnosis.
NATURE COMMUNICATIONS
(2023)
Article
Geriatrics & Gerontology
Scott P. P. Allen, Afnan Al Sultan, Elaine Kabucho Kibirige, Erin Tonkiss, Keaton J. J. Hamer, Lydia M. M. Castelli, Ya-Hui Lin, Sarah Roscoe, Nikolaos Stefanidis, Richard J. J. Mead, J. Robin Highley, Johnathan Cooper-Knock, Guillaume M. M. Hautbergue, Paul R. R. Heath, Janine Kirby, Pamela J. J. Shaw
Summary: A recent study found that truncation p.Y374X in TARDBP reduces expression of TDP43 in fibroblasts from ALS cases. In this follow-up study, we have shown that this truncation has a striking effect on the metabolic profile of fibroblasts. Phenotypic metabolic screening revealed distinct metabolic alterations in TDP43-Y374X fibroblasts, including changes in key metabolic intermediates. These findings suggest that TDP43 truncation directly impairs glycolytic and mitochondrial function, indicating potential therapeutic targets for mitigating its effects.
FRONTIERS IN AGING NEUROSCIENCE
(2023)
Article
Clinical Neurology
Allison A. Dilliott, Ahmad Al Nasser, Marwa Elnagheeb, Jennifer Fifita, Lyndal Henden, Ingrid M. Keseler, Steven Lenz, Heather Marriott, Emily Mccann, Maysen Mesaros, Sarah Opie-Martin, Emma Owens, Brooke Palus, Justyne Ross, Zhanjun Wang, Hannah White, Ammar Al-Chalabi, Peter M. Andersen, Michael Benatar, Ian Blair, Johnathan Cooper-Knock, Elizabeth A. Harrington, Jeannine Heckmann, John Landers, Cristiane Moreno, Melissa Nel, Evadnie Rampersaud, Jennifer Roggenbuck, Guy Rouleau, Bryan Traynor, Marka Van Blitterswijk, Wouter Van Rheenen, Jan Veldink, Jochen Weishaupt, Luke Drury, Matthew B. Harms, Sali M. K. Farhan
Summary: The establishment of the Clinical Genome Resource (ClinGen) amyotrophic lateral sclerosis (ALS) spectrum disorders Gene Curation Expert Panel (GCEP) aimed to evaluate the strength of evidence for genes associated with ALS. This study assessed the heterogeneity in clinical genetic testing panels for ALS and found variability in the genes included, suggesting the need for consensus on gene inclusions to improve diagnostic yields and reduce missed diagnoses. The findings highlight the importance of standardized guidance for laboratories and better application of genetic testing for ALS patients and their families.
AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION
(2023)
Article
Chemistry, Multidisciplinary
Rodrigo Ibarra-Chavez, Julien Reboud, Jose R. Penades, Jonathan M. Cooper
Summary: Phage-inducible chromosomal islands (PICIs) are genetic constructs that repurpose phage components to mobilize and spread. They have been used as antibacterial drones and a user-friendly diagnostic system based on PICI transduction has been developed for selective enrichment and detection of Escherichia coli and Staphylococcus aureus. This approach enables visual sensing of viable pathogens only, extending diagnostic sensing mechanisms beyond conventional strategies.
Article
Clinical Neurology
Cornelis Blauwendraat, Nahid Tayebi, Elizabeth Geena Woo, Grisel Lopez, Luca Fierro, Marco Toffoli, Naomi Limbachiya, Derralynn Hughes, Vanessa Pitz, Dhairya Patel, Dan Vitale, Mathew J. Koretsky, Dena Hernandez, Raquel Real, Roy N. Alcalay, Mike A. Nalls, Huw R. Morris, Anthony H. V. Schapira, Manisha Balwani, Ellen Sidransky
Summary: This study investigated the contribution of PD risk variants to risk for PD in patients with GD1. The results showed that patients with GD1 who developed PD had a significantly higher PD genetic risk score than those without PD. This suggests that common risk variants may affect underlying biological pathways.
MOVEMENT DISORDERS
(2023)