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)
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
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
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.
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.
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)
Article
Cell & Tissue Engineering
Aleksandra Beylina, Rebekah G. Langston, Dorien Rosen, Xylena Reed, Mark R. Cookson
Summary: This study presents a series of isogenic iPSC lines with different LRRK2 mutations, which can be used to assess the effects of these mutations on LRRK2 function and to study LRRK2 interactors and substrates in iPSC-derived cellular models.
STEM CELL RESEARCH
(2021)
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
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.
Article
Physiology
Seraina O. Moser, Betuel Haykir, Catharina J. Kueng, Carla Bettoni, Nati Hernando, Carsten A. Wagner
Summary: The concentration of inorganic phosphate in plasma is controlled by hormones, and saliva glands have the ability to concentrate phosphate. The parotid glands preferentially use Slc20 for phosphate transport and are potential targets for regulation by PTH and vitamin D-3.
PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY
(2023)
Editorial Material
Physiology
Carsten A. Wagner
Article
Medicine, General & Internal
Nilufar Mohebbi, Alexander Ritter, Anna Wiegand, Nicole Graf, Suzan Dahdal, Daniel Sidler, Spyridon Arampatzis, Karine Hadaya, Thomas F. Mueller, Carsten A. Wagner, Rudolf P. Wuethrich
Summary: This study examined the effects of sodium bicarbonate treatment on graft function in kidney transplant recipients. The results showed that treatment with sodium bicarbonate for two years did not affect the decline in estimated glomerular filtration rate (GFR). Therefore, sodium bicarbonate treatment is not generally recommended for preserving GFR in kidney transplant recipients with chronic kidney disease and metabolic acidosis.
Editorial Material
Transplantation
Michele Farisco, Irene Zecchino, Giovambattista Capasso, CONNECT Consortium
NEPHROLOGY DIALYSIS TRANSPLANTATION
(2023)
Article
Biochemistry & Molecular Biology
Guizhen Liu, Esther Riemer, Robin Schneider, Daniela Cabuzu, Olivier Bonny, Carsten A. A. Wagner, Danye Qiu, Adolfo Saiardi, Annett Strauss, Thomas Lahaye, Gabriel Schaaf, Thomas Knoll, Jan P. P. Jessen, Henning J. J. Jessen
Summary: The analysis of Inositol phosphates (InsPs), which are present in all eukaryotes, is challenging due to the presence of numerous different phosphate ester isomers. Researchers used capillary electrophoresis coupled to electrospray ionization mass spectrometry (CE-ESI-MS) to analyze InsP(2) and InsP(3) and discovered new InsP(3) isomers. For the first time, specific and abundant InsP(3) isomers, namely Ins(1,2,3)P-3, Ins(1,2,6)P-3, and/or Ins(2,3,4)P-3, were found in urine and kidney stones in human samples.
RSC CHEMICAL BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Pedro Henrique Imenez Silva, Donald E. Wesson, Carsten A. Wagner
Summary: Chronic kidney disease (CKD) is a disease characterized by progressive decline in kidney function. Treatments that aim to stabilize or slow its progression can delay the need for kidney replacement therapy and reduce the mortality rate associated with reduced kidney function. Metabolic acidosis and less severe stages of the acid stress continuum are common in CKD, and studies have shown that correcting these conditions can slow the progression to end-stage kidney disease. This correction can be achieved through dietary changes, such as consuming fewer acid-producing foods or more base-producing foods, or through the use of mineral alkali or pharmacological approaches.
BIOCHEMICAL SOCIETY TRANSACTIONS
(2023)
Review
Clinical Neurology
Marion Pepin, Aleksandra Klimkowicz-Mrowiec, Olivier Godefroy, Pilar Delgado, Sol Carriazo, Ana Carina Ferreira, Aleksandra Golenia, Jolanta Malyszko, Tomasz Grodzicki, Konstantinos Giannakou, Giuseppe Paolisso, Michelangela Barbieri, Liliana Garneata, Carmen Antonia Mocanu, Sophie Liabeuf, Goce Spasovski, Carmine Zoccali, Annette Bruchfeld, Ana Farinha, Mustafa Arici, Giovambattista Capasso, Andrzej A. Wiecek, Ziad Massy
Summary: Cognitive impairment is common in patients with chronic kidney disease (CKD). This article reviews interventions for the complications of CKD and prevention of vascular events, which may potentially also be protective against cognitive impairment. Nonpharmacological and pharmacological methods to prevent cognitive impairment and/or minimize its impact on CKD patients' daily lives are discussed. It is necessary to conduct studies assessing the effect of interventions on the cognitive function of patients with CKD.
EUROPEAN JOURNAL OF NEUROLOGY
(2023)
Review
Urology & Nephrology
Carsten A. Wagner, Robert Unwin, Sergio C. Lopez-Garcia, Robert Kleta, Detlef Bockenhauer, Stephen Walsh
Summary: This review discusses the underlying genetic and acquired causes of distal renal tubular acidosis (dRTA), a condition characterized by the failure to acidify urine below pH 5.5. Inherited forms of dRTA are caused by variants in specific genes such as SLC4A1 and ATP6V1B1, while acquired forms can result from autoimmune diseases or adverse drug effects. Incomplete dRTA, which is frequently found in patients with or without kidney stone disease, may represent an intermediate state in the ability to excrete acids. Untreated or unrecognized dRTA can lead to various complications such as rickets, osteomalacia, nephrolithiasis, and electrolyte disorders, and increase the risk of chronic kidney disease development.
NATURE REVIEWS NEPHROLOGY
(2023)
Article
Multidisciplinary Sciences
H. Vitzthum, M. Koch, L. Eckermann, S. L. Svendsen, P. Berg, C. A. Huebner, C. A. Wagner, J. Leipziger, C. Meyer-Schwesinger, H. Ehmke
Summary: Maintaining acid-base balance is important for the kidneys, and the solute transporter AE4 in beta-intercalated cells is found to play a role in renal acid-base sensing mechanism.
NATURE COMMUNICATIONS
(2023)
Article
Medicine, Research & Experimental
Nima Yassini, Janine Sprenger, Eva Maria Pastor Arroyo, Christiane Krudewig, Giovanni Pellegrini, Nicole Joller, Carsten A. Wagner, Pedro Henrique Imenez Silva
Summary: Ovarian cancer G protein-coupled receptor 1 (OGR1) and G protein-coupled receptor 4 (GPR4) play important roles in renal acid-base physiology, tissue inflammation, and fibrosis. In this study, the researchers found that OGR1 deficiency led to increased crystal deposition and impaired kidney function in mice with crystalline nephropathy. On the other hand, GPR4 deficiency did not have a significant impact on disease progression. These findings suggest that OGR1 may be important in limiting kidney crystal deposition and could be relevant to the pathophysiology of kidney stones.
Article
Neurosciences
Basma Sukkar, Lalehan Oktay, Ayse Sahaboglu, Aylin Moayedi, Shima Zenouri, Tamer Al-Maghout, Antolin Canto, Maria Miranda, Serdar Durdagi, Zohreh Hosseinzadeh
Summary: Inhibition of Orai1 channel and SOCE in MGCs can protect photoreceptors from degeneration, suggesting that they could be potential therapeutic targets.
Article
Endocrinology & Metabolism
Rocio Fuente, Eva-Maria Pastor-Arroyo, Nicole Gehring, Patricia Oro Carbajosa, Laura Alonso-Duran, Ivan Zderic, James Tapia-Dean, Ahmad Kamal Hamid, Carla Bettoni, Fernando Santos, Carsten A. Wagner, Isabel Rubio-Aliaga
Summary: This study examines the role of FGF23 signaling in growth plate metabolism and finds that a short C-terminal FGF23 fragment and modified peptides can improve growth and bone issues in XLH patients, enhancing growth rate and growth plate structure.
JOURNAL OF ENDOCRINOLOGY
(2023)
Article
Neurosciences
Yogesh Singh, Christoph Trautwein, Joan Romani, Madhuri S. S. Salker, Peter H. H. Neckel, Isabel Fraccaroli, Mahkameh Abeditashi, Nils Woerner, Jakob Admard, Achal Dhariwal, Morten K. D. Dueholm, Karl-Herbert Schaefer, Florian Lang, Daniel E. E. Otzen, Hilal A. A. Lashuel, Olaf Riess, Nicolas Casadei
Summary: Braak's hypothesis suggests that the progression of Parkinson's disease from the peripheral to the central nervous system can be monitored by detecting the accumulation of alpha-Synuclein protein. This study used various techniques to investigate the role of the gut microbiome in regulating alpha-Synuclein accumulation and found that dysbiosis of the gut microbiome can contribute to Parkinson's disease pathology.
MOLECULAR NEURODEGENERATION
(2023)
Article
Physiology
Thomas Verissimo, Delal Dalga, Gregoire Arnoux, Imene Sakhi, Anna Faivre, Hannah Auwerx, Soline Bourgeois, Deborah Paolucci, Quentin Gex, Joseph M. Rutkowski, David Legouis, Carsten A. Wagner, Andrew M. Hall, Sophie de Seigneux
Summary: Phosphoenolpyruvate carboxykinase 1 (PCK1) plays an important role in maintaining normal tubular physiology, lactate, and glucose homeostasis in the kidney. It regulates acid-base balance and ammoniagenesis. Downregulation of PCK1 during renal injury impairs renal function, making it a potential therapeutic target in renal disease.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2023)
Article
Urology & Nephrology
Soline Bourgeois, Jana Kovacikova, Milica Bugarski, Carla Bettoni, Nicole Gehring, Andrew Hall, Carsten A. Wagner
Summary: This study reveals the critical role of H+-ATPases in the function of non-type A intercalated cells (ICs) in protecting against alkalosis. It also highlights the previously unrecognized need for the basolateral B1 isoform for proper assembly and stimulation of H+-ATPase complexes.
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
(2023)
