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
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
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
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
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
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
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
Neurosciences
George Tsafaras, Veerle Baekelandt
Summary: Parkinson's disease is considered a multisystemic disorder rather than a pure brain disease. There is increasing evidence that the pathology may originate in the periphery, but unknown aspects and contradictory data on peripheral pathological processes hinder the interpretation and treatment of Parkinson's disease. Mutations in the LRRK2 gene have been linked to Parkinson's disease, but the actual role of LRRK2 in its pathophysiology is not well understood.
NEUROBIOLOGY OF DISEASE
(2022)
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.
Article
Geriatrics & Gerontology
Peng-Hsiang Liao, Han-Lin Chiang, Chia-Tung Shun, Jen-Fan Hang, Han-Mo Chiu, Ming-Shiang Wu, Chin-Hsien Lin
Summary: This study investigated the expression of LRRK2 in colonic biopsies obtained from PD patients and healthy controls. The results showed that the fraction of LRRK2-positive cells was significantly higher in PD patients compared to controls, and individuals with LRRK2 genetic variants had higher colonic LRRK2 immunoreactivity. LRRK2 expression correlated with disease severity, and PD patients in the prodromal phase had a faster increase in colonic LRRK2 expression.
FRONTIERS IN AGING NEUROSCIENCE
(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)
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
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
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.
Review
Clinical Neurology
Ayan Hussein, Christopher A. Guevara, Pamela Del Valle, Swati Gupta, Deanna L. Benson, George W. Huntley
Summary: Parkinson's disease is a neurodegenerative disorder characterized by motor impairment. However, there are also non-motor symptoms such as depression, anxiety, and cognitive impairment, which can appear earlier than motor symptoms. The neurobiology underlying these non-motor symptoms is not completely understood, but genetic models in animals have provided insights into the cellular and synaptic mechanisms involved. Recent studies also highlight the role of brain-immune signaling crosstalk in modulating brain cell and synaptic function in relation to psychiatric symptoms.
Article
Neurosciences
Connie Mackenzie-Gray Scott, R. Ryley Parrish, Darren Walsh, Claudia Racca, Rita M. Cowell, Andrew J. Trevelyan
Summary: The study demonstrates that knocking down the transcriptional coactivator PGC-1 alpha in PV-expressing cells in the cortical network produces an antiepileptic effect, reducing the activity of epileptic discharges and extending the period before the onset of seizure events.
JOURNAL OF NEUROPHYSIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Stephanie M. Boas, Kathlene L. Joyce, Rita M. Cowell
Summary: This article reviews the biology of NFE2/NRF transcription factor family in the brain and the cellular localization of NFE2/NRF family members in nervous system cells. It discusses the relationship between these findings and oxidative stress observed in Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS), and presents strategies for activating NFE2/NRF-dependent transcription. Based on the expression of NFE2/NRF family members in specific populations of neurons and glia, the authors propose considering the relative contributions of different cell types to the overall oxidative state when designing neuroprotection strategies.
Article
Biochemistry & Molecular Biology
Sourav Kolay, Anthony R. Vega, Dana A. Dodd, Valerie A. Perez, Omar M. Kashmer, Charles L. White, Marc I. Diamond
Summary: Movement of Tau assemblies from extracellular to intracellular space may play a role in the transcellular propagation of neurodegenerative tauopathies. Tau binds to cell surface heparan sulfate proteoglycans, triggering macropinocytosis. Pathological tau assemblies may exit vesicles and replicate in the cytoplasm as seeds. Most exogenous tau is trafficked to the lysosome, but a small fraction accumulates in the cytosol. Tau seeds have two fates: lysosomal clearance or entry into the cytosol for amplification and clearance by the proteasome.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Correction
Neurosciences
L. J. McMeekin, K. L. Joyce, L. M. Jenkins, B. M. Bohannon, K. D. Patel, A. S. Bohannon, A. Patel, S. N. Fox, M. S. Simmons, J. J. Day, A. Kralli, D. K. Crossman, R. M. Cowell
Article
Neurosciences
Daniel R. Wong, Ziqi Tang, Nicholas C. Mew, Sakshi Das, Justin Athey, Kirsty E. McAleese, Julia K. Kofler, Margaret E. Flanagan, Ewa Borys, Charles L. White, Atul J. Butte, Brittany N. Dugger, Michael J. Keiser
Summary: This study presents a deep learning approach that incorporates the expertise of multiple pathologists to address the challenge of inconsistent labeling of pathologies. The results show significant improvements in pathology diagnosis using the consensus of two strategy in training deep learning models. In blind tests, the models labeled pathologies consistently with human experts.
ACTA NEUROPATHOLOGICA COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Gelare Ghajar-Rahimi, Amie M. Traylor, Bini Mathew, James R. Bostwick, N. Miranda Nebane, Anna A. Zmijewska, Stephanie K. Esman, Saakshi Thukral, Ling Zhai, Vijaya Sambandam, Rita M. Cowell, Mark J. Suto, James F. George, Corinne E. Augelli-Szafran, Anupam Agarwal
Summary: Acute kidney injury is a major health concern with no current effective treatments. This study identifies small-molecule inducers of HO-1 as potential therapeutic candidates for AKI.
Article
Neurosciences
S. N. Fox, L. J. McMeekin, C. H. Savage, K. L. Joyce, S. M. Boas, M. S. Simmons, C. B. Farmer, J. Ryan, L. Pereboeva, K. Becker, J. Auwerx, S. Sudarshan, J. Ma, A. Lee, R. C. Roberts, D. K. Crossman, A. Kralli, R. M. Cowell
Summary: ERR γ plays a crucial role in dopaminergic neurons and its deficiency is associated with reductions in mitochondrial function, synaptic genes, and autophagy-related genes, potentially serving as a model for PD.
NPJ PARKINSONS DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Charlotte H. Hurst, Dionne Turnbull, Kaltra Xhelilaj, Sally Myles, Robin L. Pflughaupt, Michaela Kopischke, Paul Davies, Susan Jones, Silke Robatzek, Cyril Zipfel, Julien Gronnier, Piers A. Hemsley
Summary: Plant receptor kinases play a crucial role in transducing extracellular stimuli and are regulated by post-translational modifications. This study demonstrates the essential role of S-acylation in plant receptor kinases FLS24 and EFR for their function in immune signaling and resistance to bacterial infection. S-acylation stabilizes and promotes retention of activated receptor kinase complexes at the plasma membrane to increase signaling efficiency.
Editorial Material
Clinical Neurology
Andrew B. West, Michael A. Schwarzschild
MOVEMENT DISORDERS
(2023)
Article
Neurosciences
Mahendra Singh, Kiran Sapkota, Kenji Sakimura, Masanobu Kano, Rita M. Cowell, Linda Overstreet-Wadiche, John J. Hablitz, Kazu Nakazawa
Summary: Hypofunction of the NMDAR receptor during brain development may contribute to the onset of schizophrenia in young adults. The cellular targets of NMDAR hypofunction include corticolimbic fast-spiking interneurons. However, the functional alterations in PV-positive FS interneurons following NMDAR hypofunction are not well understood.
Article
Multidisciplinary Sciences
Vishruth Mullapudi, Jaime Vaquer-Alicea, Vaibhav Bommareddy, Anthony R. Vega, Bryan D. Ryder, Charles L. White, Marc. I. Diamond, Lukasz A. Joachimiak
Summary: Cryogenic electron microscopy has provided new insights into the conformations of beta-sheet-rich protein amyloids related to neurodegenerative diseases. By using an in silico alanine scan method, the relative energetic contributions of each amino acid in amyloid assembly can be estimated. Applying this method to various fibril structural polymorphs of tau protein, networks of energetically important interactions that stabilize different fibril folds are identified. These findings have implications for the future design of protein sequences that can fold into unique structures.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
John M. Hatcher, Monika Zwirek, Adil R. Sarhan, Prasanna S. Vatsan, Francesca Tonelli, Dario R. Alessi, Paul Davies, Nathanael S. Gray
Summary: The use of proteolysis-targeting chimeras (PROTACs) targeting LRRK2 offers a promising new approach for the treatment of Parkinson's Disease by eliminating both the kinase activity and scaffolding function of LRRK2.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Clinical Neurology
Lyndsay Hastings, Arpine Sokratian, Daniel J. Apicco, Christina M. Stanhope, Lindsey Smith, Warren D. Hirst, Andrew B. West, Kaela Kelly
Summary: This study evaluated the effects of poly(ADP-ribose) polymer and ABT-888 on the fibrillation of alpha-synuclein, as well as their effects on the formation of alpha-synuclein inclusions and neurodegeneration. The results showed that poly(ADP-ribose) polymer minimally increased the rate of alpha-synuclein fibril formation. However, ABT-888 did not have a significant impact on the inclusion counts and dopaminergic cell loss.
BRAIN COMMUNICATIONS
(2022)
Correction
Neurosciences
Mark S. Moehle, Philip J. Webber, Tonia Tse, Nour Sukar, David G. Standaert, Tara M. DeSilva, Rita M. Cowell, Andrew B. West
JOURNAL OF NEUROSCIENCE
(2022)