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.
Review
Biochemistry & Molecular Biology
Tatou Iseki, Yuzuru Imai, Nobutaka Hattori
Summary: Leucine rich-repeat kinase 2 (LRRK2) is the most well-known genetic cause of familial Parkinson's disease (PD). Its functions and relationship to the pathogenesis of PD are not fully understood. Recent studies have suggested that LRRK2 plays a role in glial cell dysfunction and neurodegeneration, particularly in lysosomal dynamics and inflammation. This review discusses the proposed functions of LRRK2 in glial cells and its involvement in the pathomechanisms of 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.
Review
Biochemistry & Molecular Biology
Luis Bonet-Ponce, Mark R. Cookson
Summary: Protein coding mutations in LRRK2 cause familial Parkinson's disease, while noncoding variations increase the risk of sporadic PD. These mutations increase LRRK2 kinase activity, influencing intracellular membrane trafficking.
Article
Cell Biology
Adrienne E. D. Stormo, Farbod Shavarebi, Molly FitzGibbon, Elizabeth M. Earley, Hannah Ahrendt, Lotus S. Lum, Erik Verschueren, Danielle L. Swaney, Gaia Skibinski, Abinaya Ravisankar, Jeffrey van Haren, Emily J. Davis, Jeffrey R. Johnson, John Von Dollen, Carson Balen, Jacob Porath, Claudia Crosio, Christian Mirescu, Ciro Iaccarino, William T. Dauer, R. Jeremy Nichols, Torsten Wittmann, Timothy C. Cox, Steve Finkbeiner, Nevan J. Krogan, Scott A. Oakes, Annie Hiniker
Summary: This study reveals that TRIM1 plays a critical role in regulating the degradation, localization, and kinase activity of LRRK2, which is crucial for familial Parkinson's disease.
JOURNAL OF CELL BIOLOGY
(2022)
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
Clinical Neurology
Anke Van der Perren, Diego Cabezudo, Geraldine Gelders, Javier M. Peralta Ramos, Chris Van den Haute, Veerle Baekelandt, Evy Lobbestael
Summary: The development of disease-modifying therapies for Parkinson's disease faces challenges, as the relationship between LRRK2 and alpha-synuclein in the disease remains unresolved. Studies show that total loss of LRRK2 or pharmacological inhibition did not significantly impact motor deficits or dopaminergic cell loss induced by alpha-synuclein, but did affect neuroinflammation. Further research is needed to understand the connection between neuroinflammatory processes and disease progression in Parkinson's disease.
Article
Chemistry, Multidisciplinary
Weitong Cui, Xiao Yang, Xingyu Chen, Dexuan Xiao, Junyao Zhu, Mei Zhang, Xin Qin, Xiaohong Ma, Yunfeng Lin
Summary: Vitamin B12 is a promising therapeutic option for Parkinson's disease (PD) due to its ability to inhibit LRRK2 activity, but its therapeutic effects are limited by transporter dependence and low brain tissue utilization. Researchers have synthesized VB12-loaded tetrahedral framework nucleic acid (TVC), which has shown to provide better recovery of autophagy and improvement of symptoms in PD models, indicating broad therapeutic potential for PD and similar neurodegenerative diseases.
ADVANCED FUNCTIONAL MATERIALS
(2021)
Article
Biochemistry & Molecular Biology
Kyohei Ito, Miho Araki, Yuta Katai, Yuki Nishimura, Sota Imotani, Haruki Inoue, Genta Ito, Taisuke Tomita
Summary: Mutations in LRRK2 cause familial Parkinson's disease (PD). Overexpression of pathogenic mutant LRRK2 leads to clustering of lysosomes in the perinuclear region, dependent on its kinase activity. The phosphorylation of Rab12 by LRRK2 enhances its interaction with RILPL1, compromising intracellular lysosomal transport and suggesting a role in LRRK2-mediated PD pathogenesis.
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
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)
Article
Cell Biology
Dong-Hwan Ho, Daleum Nam, Mikyoung Seo, Sung-Woo Park, Wongi Seol, Ilhong Son
Summary: Research suggests that LRRK2 inhibitors could be a novel therapeutic approach against alpha Syn-mediated Parkinson's disease progression. By inhibiting LRRK2 activity, the neuroinflammatory responses caused by neuron-released alpha Syn in microglia cells can be alleviated, thus slowing down the progression of PD.
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)
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)
Review
Cell Biology
Patrick D. Skelton, Valerie Tokars, Loukia Parisiadou
Summary: Mutations in the LRRK2 gene can lead to Parkinson's disease with similar clinical presentation and progression to idiopathic Parkinson's disease, making it a valuable model for understanding the pathobiology of the disease. Studies suggest that pathogenic LRRK2 mutations disrupt synapses in striatal neurons, which has significant implications for the development of neurodegenerative diseases.