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
Vinita G. Chittoor-Vinod, R. Jeremy Nichols, Birgitt Schule
Summary: Missense mutations in the LRRK2 gene are a pathogenic cause of Parkinson's disease, with approximately 100,000 individuals worldwide carrying the risk variant. Clinical presentation of LRRK2 parkinsonism is similar to sporadic PD but varies in disease penetrance and age at onset, with neuropathological features ranging from nigrostriatal loss with Lewy body pathology to atypical neuropathology, including cases of concomitant Alzheimer's pathology.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Clinical Neurology
Maria Rosario Almeida, Ana Rita Silva, Ines Elias, Carolina Fernandes, Rita Machado, Orlando Galego, Gustavo Cordeiro Santo
Summary: CADASIL, caused by NOTCH3 mutations, shows phenotypic variability even with the same pathogenic variant. Two siblings with aggressive clinical phenotype carried NOTCH3 and SQSTM1 pathogenic variants, potentially exacerbating disease progression. Contribution of SQSTM1 to clinical heterogeneity in CADASIL patients, particularly those with early cognitive impairment, is highlighted, suggesting the need for expanded genetic analysis.
JOURNAL OF NEUROLOGY
(2021)
Article
Geriatrics & Gerontology
Emmeline E. Brown, Cornelis Blauwendraat, Joanne Trinh, Mie Rizig, Mike A. Nalls, Etienne Leveille, Jennifer A. Ruskey, Hallgeir Jonvik, Manuela M. X. Tan, Sara Bandres-Ciga, Sharon Hassin-Baer, Kathrin Brockmann, Jon Infante, Eduardo Tolosa, Mario Ezquerra, Sawssan Ben Romdhan, Mustapha Benmahdjoub, Mohamed Arezki, Chokri Mhiri, John Hardy, Andrew B. Singleton, Roy N. Alcalay, Thomas Gasser, Donald G. Grosset, Nigel M. Williams, Alan Pittman, Ziv Gan-Or, Ruben Fernandez-Santiago, Alexis Brice, Suzanne Lesage, Matthew Farrer, Nicholas Wood, Huw R. Morris
Summary: The LRRK2 gene is associated with rare and common risk variants for Parkinson's disease, while DNM3 and VAMP4 may also play a role in disease risk. However, more research is needed to understand the specific mechanisms involved.
NEUROBIOLOGY OF AGING
(2021)
Review
Neurosciences
Pedro Magalhaes, Hilal A. Lashuel
Summary: This review provides an overview of the distribution of alpha-synuclein (aSyn) species in the brain, peripheral tissues, and biological fluids. It analyses previous studies on measuring total aSyn and other modified and aggregated forms of aSyn in different biological fluids. It highlights the conceptual and technical gaps and challenges in developing and validating reliable aSyn biomarkers and proposes recommendations to address these challenges.
NPJ PARKINSONS DISEASE
(2022)
Article
Clinical Neurology
Tatiana Usnich, Eva-Juliane Vollstedt, Nathalie Schell, Volha Skrahina, Xenia Bogdanovic, Hanaa Gaber, Toni M. Foerster, Andreas Heuer, Natalia Koleva-Alazeh, Ilona Csoti, Ayse Nazli Basak, Sibel Ertan, Gencer Genc, Peter Bauer, Katja Lohmann, Anne Gruenewald, Emma L. Schymanski, Joanne Trinh, Susen Schaake, Daniela Berg, Doreen Gruber, Stuart H. Isaacson, Andrea A. Kuehn, Brit Mollenhauer, David J. Pedrosa, Kathrin Reetz, Esther M. Sammler, Enza Maria Valente, Franco Valzania, Jens Volkmann, Simone Zittel, Norbert Brueggemann, Meike Kasten, Arndt Rolfs, Christine Klein
Summary: The LIPAD project aims to systematically assess clinical signs and symptoms in PD patients, unaffected LRRK2 pathogenic variant carriers, and controls, and investigate modifiers of penetrance and expressivity of LRRK2 pathogenic variants using genetic and environmental data.
FRONTIERS IN NEUROLOGY
(2021)
Editorial Material
Immunology
Youcui Wang, Xiaoqin Zhang, Fenghua Chen, Leilei Chen, Jun Wang, Junxia Xie
Summary: Neuroinflammation is crucial in the pathogenesis of Parkinson's disease. Modulation of the LRRK2-NFATc2 signaling cascade in microglia could be a potential therapeutic target for PD treatment. The activation of LRRK2 by neuron-released alpha-synuclein via TLR2 leads to a neurotoxic inflammatory environment.
JOURNAL OF INFLAMMATION RESEARCH
(2021)
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)
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 found that PD patients with GD1 have a higher genetic risk score, suggesting that common risk variants may affect underlying biological pathways.
MOVEMENT DISORDERS
(2023)
Article
Chemistry, Medicinal
Solomon D. Kattar, Anmol Gulati, Kaila A. Margrey, Mitchell H. Keylor, Michael Ardolino, Xin Yan, Rebecca Johnson, Rachel L. Palte, Spencer E. McMinn, Lisa Nogle, Jing Su, Dong Xiao, Jennifer Piesvaux, Susi Lee, Laxminarayan G. Hegde, Janice D. Woodhouse, Robert Faltus, Lily Y. Moy, Tina Xiong, Paul J. Ciaccio, Kara Pearson, Mayankbhai Patel, Karin M. Otte, Cheryl E. G. Leyns, Matthew E. Kennedy, David Jonathan Bennett, Erin F. Dimauro, Matthew J. Fell, Peter H. Fuller
Summary: A novel LRRK2 inhibitor with favorable CNS drug-like properties was discovered, and further optimization resulted in a promising preclinical candidate.
JOURNAL OF MEDICINAL CHEMISTRY
(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
Biochemistry & Molecular Biology
Richard Agren, Snehal Patil, Xiang Zhou, FinnGen, Kristoffer Sahlholm, Svante Paabo, Hugo Zeberg
Summary: Dupuytren's disease is a condition where fingers become permanently bent. It is more common in men over 60 years old in northern Europe, but rare in people of African ancestry. Through analyzing 3 biobanks with 7,871 cases and 645,880 controls, researchers found 61 genome-wide significant variants associated with Dupuytren's disease. Importantly, three of these variants have Neandertal origins, including the two most strongly associated ones. The study also identified EPDR1 as the causal gene for the strongest Neandertal variant. This highlights how admixture with Neandertals has influenced regional differences in disease prevalence.
MOLECULAR BIOLOGY AND EVOLUTION
(2023)
Article
Biochemistry & Molecular Biology
Megha Rajendran, Maria Queralt-Martin, Philip A. Gurnev, William M. Rosencrans, Amandine Rovini, Daniel Jacobs, Kaitlin Abrantes, David P. Hoogerheide, Sergey M. Bezrukov, Tatiana K. Rostovtseva
Summary: This study discovered a small membrane-binding peptide, called HK2p, that inhibits the complex formation of alpha-synuclein (alpha Syn) with the voltage-dependent anion channel (VDAC). The peptide attenuates the mitochondrial toxicity caused by alpha Syn, suggesting a potential therapeutic avenue for Parkinson's disease and other synucleinopathies.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2022)
Article
Geriatrics & Gerontology
Yuwan Lin, Miaomiao Zhou, Wei Dai, Wenyuan Guo, Jiewen Qiu, Zhiling Zhang, Mingshu Mo, Liuyan Ding, Panghai Ye, Yijuan Wu, Xiaoqin Zhu, Zhuohua Wu, Pingyi Xu, Xiang Chen
Summary: Plasma levels of OCN and OPN in PD patients are correlated with inflammation response, disease stage, and motor impairment, making them potential biomarkers for PD. The combination of plasma assessment and CSF detection enhances predictive ability for PD.
FRONTIERS IN AGING NEUROSCIENCE
(2021)
Article
Biochemistry & Molecular Biology
Anna S. Vetchinova, Marina R. Kapkaeva, Mikhail V. Ivanov, Kristina A. Kutukova, Natalia M. Mudzhiri, Lydia E. Frumkina, Anatoly V. Brydun, Vladimir S. Sukhorukov, Sergey N. Illarioshkin
Summary: Parkinson's disease is a common neurodegenerative disease that can be caused by genetic factors. Induced pluripotent stem cell technology provides new opportunities for studying biomarkers of Parkinson's disease. Gene expression analysis and electron microscopy revealed differences in mitochondrial structure and activity between diseased and normal cells.
CURRENT ISSUES IN MOLECULAR BIOLOGY
(2023)
