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
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
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)
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
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)
Article
Biochemistry & Molecular Biology
Chen Dong, Chandrashekhar Honrao, Leonardo O. Rodrigues, Josephine Wolf, Keri B. Sheehan, Matthew Surface, Roy N. Alcalay, Elizabeth M. O'Day
Summary: Parkinson's disease is a progressive neurodegenerative disease with motor and nonmotor function loss. This study identified metabolic markers of PD in plasma and developed a machine learning model for PD diagnosis with high accuracy. The findings provide insights for the development of diagnostic tools for PD.
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
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)
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)
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
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
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
Clinical Neurology
Julie Lake, Xylena Reed, Rebekah G. Langston, Mike A. Nalls, Ziv Gan-Or, Mark R. Cookson, Andrew B. Singleton, Cornelis Blauwendraat, Hampton L. Leonard
Summary: This study conducted a large meta-analysis to investigate the association of LRRK2 rs76904798 with PD risk independently from LRRK2 coding variation, showing that rs76904798 remained significantly associated with PD after excluding carriers of relatively rare LRRK2 coding variants. The study also found that LRRK2 coding variants previously related to PD do not drive the 5' noncoding GWAS signal, suggesting an independent association of certain haplotypes with altered disease risk.
MOVEMENT DISORDERS
(2022)
Article
Multidisciplinary Sciences
Nobutaka Hattori, Atsushi Takeda, Yuki Hanya, Tadayuki Kitagawa, Masaki Arai, Yoshihiko Furusawa, Hideki Mochizuki, Masahiro Nagai, Ryosuke Takahashi
Summary: This study investigated the mechanism of how rasagiline affects the emotional well-being domain of PDQ-39 in Japanese patients with Parkinson's disease. The results showed that the effects of rasagiline on the emotional well-being domain were primarily mediated by its influence on the subjective aspects of motor experiences of daily living.
Letter
Clinical Neurology
Hikaru Kamo, Genko Oyama, Kenya Nishioka, Manabu Funayama, Nobutaka Hattori
MOVEMENT DISORDERS CLINICAL PRACTICE
(2022)
Review
Genetics & Heredity
Manabu Funayama, Kenya Nishioka, Yuanzhe Li, Nobutaka Hattori
Summary: Parkinson's disease is a neurodegenerative disorder primarily characterized by motor dysfunction. Genetic factors, in addition to aging and environmental factors, play an important role in the development of the disorder. Familial PD has identified approximately 20 causative genes, while sporadic PD has over 200 potential driver genes.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Genetics & Heredity
Hao Peng, Yuanzhe Li, Hiroyo Yoshino, Mai Shimizu, Kenya Nishioka, Manabu Funayama, Nobutaka Hattori
Summary: A recent study reported that a heterozygous loss-of-function variant in LIN28A was a novel pathogenic gene in PD patients from Korea. However, this study aimed to determine the prevalence of LIN28A variants among Japanese PD patients and found no strong association between LIN28A and early-onset PD in this population.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Clinical Neurology
Eva-Juliane Vollstedt, Susen Schaake, Katja Lohmann, Shalini Padmanabhan, Alexis Brice, Suzanne Lesage, Christelle Tesson, Marie Vidailhet, Isabel Wurster, Faycel Hentati, Anat Mirelman, Nir Giladi, Karen Marder, Cheryl Waters, Stanley Fahn, Meike Kasten, Norbert Bruggemann, Max Borsche, Tatiana Foroud, Eduardo Tolosa, Alicia Garrido, Grazia Annesi, Monica Gagliardi, Maria Bozi, Leonidas Stefanis, Joaquim J. Ferreira, Leonor Correia Guedes, Micol Avenali, Simona Petrucci, Lorraine Clark, Ekaterina Y. Fedotova, Natalya Y. Abramycheva, Victoria Alvarez, Manuel Menendez-Gonzalez, Silvia Jesus Maestre, Pilar Gomez-Garre, Pablo Mir, Andrea Carmine Belin, Caroline Ran, Chin-Hsien Lin, Ming-Che Kuo, David Crosiers, Zbigniew K. Wszolek, Owen A. Ross, Joseph Jankovic, Kenya Nishioka, Manabu Funayama, Jordi Clarimon, Caroline H. Williams-Gray, Marta Camacho, Mario Cornejo-Olivas, Luis Torres-Ramirez, Yih-Ru Wu, Guey-Jen Lee-Chen, Ana Morgadinho, Teeratorn Pulkes, Pichet Termsarasab, Daniela Berg, Gregor Kuhlenbaumer, Andrea A. Kuhn, Friederike Borngraeber, Giuseppe de Michele, Anna De Rosa, Alexander Zimprich, Andreas Puschmann, George D. Mellick, Jolanta Dorszewska, Jonathan Carr, Rosangela Ferese, Stefano Gambardella, Bruce Chase, Katerina Markopoulou, Wataru Satake, Tatsushi Toda, Malco Rossi, Marcelo Merello, Timothy Lynch, Diana A. Olszewska, Shen-Yang Lim, Azlina Ahmad-Annuar, Ai Huey Tan, Bashayer Al-Mubarak, Hasmet Hanagasi, Dariusz Koziorowski, Sibel Ertan, Gencer Genc, Patricia de Carvalho Aguiar, Melinda Barkhuizen, Marcia M. G. Pimentel, Rachel Saunders-Pullman, Bart van de Warrenburg, Susan Bressman, Mathias Toft, Silke Appel-Cresswell, Anthony E. Lang, Matej Skorvanek, Agnita J. W. Boon, Rejko Kruger, Esther M. Sammler, Vitor Tumas, Bao-Rong Zhang, Gaetan Garraux, Sun Ju Chung, Yun Joong Kim, Juliane Winkelmann, Carolyn M. Sue, Eng-King Tan, Joana Damasio, Peter Klivenyi, Vladimir S. Kostic, David Arkadir, Mika Martikainen, Vanderci Borges, Jens Michael Hertz, Laura Brighina, Mariana Spitz, Oksana Suchowersky, Olaf Riess, Parimal Das, Brit Mollenhauer, Emilia M. Gatto, Maria Skaalum Petersen, Nobutaka Hattori, Ruey-Meei Wu, Sergey N. Illarioshkin, Enza Maria Valente, Jan O. Aasly, Anna Aasly, Roy N. Alcalay, Avner Thaler, Matthew J. Farrer, Kathrin Brockmann, Jean-Christophe Corvol, Christine Klein
Summary: Through a worldwide online survey, we established an international cohort of individuals with PD-linked variants, providing harmonized and quality-controlled clinical and genetic data for each participant and promoting collaboration among researchers in the field of monogenic PD.
MOVEMENT DISORDERS
(2023)
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
Biochemistry & Molecular Biology
Ayami Okuzumi, Taku Hatano, Gen Matsumoto, Shuko Nojiri, Shin-ichi Ueno, Yoko Imamichi-Tatano, Haruka Kimura, Soichiro Kakuta, Akihide Kondo, Takeshi Fukuhara, Yuanzhe Li, Manabu Funayama, Shinji Saiki, Daisuke Taniguchi, Taiji Tsunemi, Deborah McIntyre, Jean-Jacques Gerardy, Michel Mittelbronn, Rejko Kruger, Yasuo Uchiyama, Nobuyuki Nukina, Nobutaka Hattori
Summary: A modified assay system (IP/RT-QuIC) has been developed to detect pathogenic alpha-synuclein seeds in the serum of individuals with synucleinopathies. The system showed high diagnostic performance for differentiating Parkinson's disease and multiple system atrophy from controls.
Article
Medicine, General & Internal
Nobutaka Hattori, Yoshiko Okada, Yayoi Kawata, Yoshihiko Furusawa, Takumi Imai, Hisako Yoshida, Mihoko Ota, Masaki Arai, Ayumi Shintani, Jovelle Fernandez
Summary: This study aimed to investigate the impact of the COVID-19 pandemic on patients with Parkinson's disease and their caregivers in Japan. The results showed that over 40% of patients reduced their frequency of going out, approximately 7-30% experienced worsened symptoms, and caregivers reported increased burden. The findings suggest the importance of providing support to patients and caregivers during infectious disease epidemics to alleviate their burden.
PATIENT PREFERENCE AND ADHERENCE
(2023)
Article
Biochemistry & Molecular Biology
Yuri Yamashita, Satoshi Nakada, Kyoko Nakamura, Hidetoshi Sakurai, Kinji Ohno, Tomohide Goto, Yo Mabuchi, Chihiro Akazawa, Nobutaka Hattori, Eri Arikawa-Hirasawa
Summary: Schwartz-Jampel syndrome (SJS) is a rare genetic disorder characterized by myotonia. In this study, a cellular model of SJS was created using patient-derived induced pluripotent stem cells, which showed hyper-responsiveness to acetylcholine. These findings confirmed the use of cellular models in studying SJS and evaluating myotonia in clinical cases.
Editorial Material
Clinical Neurology
Nobutaka Hattori
NEURODEGENERATIVE DISEASE MANAGEMENT
(2023)
Article
Clinical Neurology
Kensuke Daida, Manabu Funayama, Kimberley J. Billingsley, Laksh Malik, Abigail Miano-Burkhardt, Hampton L. Leonard, Mary B. Makarious, Hirotaka Iwaki, Jinhui Ding, J. Raphael Gibbs, Mayu Ishiguro, Hiroyo Yoshino, Kotaro Ogaki, Genko Oyama, Kenya Nishioka, Risa Nonaka, Wado Akamatsu, Cornelis Blauwendraat, Nobutaka Hattori
Summary: This study identified a large novel 7 Mb inversion involving PRKN, which is associated with young-onset Parkinson's disease. Long-read sequencing proved to be valuable for detecting complex structural variants in unresolved PD cases. The findings highlight the importance of investigating structural variants in PRKN using advanced sequencing technologies.
MOVEMENT DISORDERS
(2023)
Article
Clinical Neurology
Christina Andica, Koji Kamagata, Wataru Uchida, Yuya Saito, Kaito Takabayashi, Akifumi Hagiwara, Haruka Takeshige-Amano, Taku Hatano, Nobutaka Hattori, Shigeki Aoki
Summary: This study compared the white matter differences between nonmedicated patients with early-stage GBA-PD and iPD using a novel technique, fixel-based analysis. The results showed that patients with GBA-PD had lower white matter density, while patients with iPD had larger white matter fiber bundles. These findings may be related to neurodegenerative diseases, α-synuclein accumulation, and cognitive and motor impairments.
MOVEMENT DISORDERS
(2023)
Article
Neurosciences
Amica C. Mueller-Nedebock, Marieke C. J. Dekker, Matthew J. Farrer, Nobutaka Hattori, Shen-Yang Lim, George D. Mellick, Irena Rektorova, Mohamed Salama, Artur F. S. Schuh, A. Jon Stoessl, Carolyn M. Sue, Ai Huey Tan, Rene L. Vidal, Christine Klein, Soraya Bardien
Summary: The biological basis of Parkinson's disease, a neurodegenerative movement disorder, is still unclear despite being discovered over 200 years ago. This article summarizes the viewpoints of PD experts on the different theories regarding its pathobiology.
NPJ PARKINSONS DISEASE
(2023)
Article
Neurosciences
Wataru Sako, Yuki Kogo, Michinori Koebis, Yoshiaki Kita, Hajime Yamakage, Takayuki Ishida, Nobutaka Hattori
Summary: This study compared the efficacy, tolerability, and safety of different classes of anti-PD drugs in patients with fluctuating PD who were receiving levodopa. The results showed that ropinirole, pramipexole, and safinamide are well-balanced anti-PD drugs that have both good efficacy and tolerability.
NPJ PARKINSONS DISEASE
(2023)
Article
Biology
Davide Cossu, Yuji Tomizawa, Kazumasa Yokoyama, Tamami Sakanishi, Eiichi Momotani, Leonardo A. Sechi, Nobutaka Hattori
Summary: The study analyzed the levels of different IgG subclasses in the blood of Japanese and Italian individuals with relapsing remitting multiple sclerosis (MS) in response to MAP-derived peptides. The study also examined the effects of MAP peptides on MOG-induced experimental autoimmune encephalomyelitis (EAE) in mice. The results suggest a potential link between MAP and the development or exacerbation of MS, particularly in individuals with elevated serum IgG4 levels.