Editorial Material
Cell Biology
Rayan Fakih, Veronique Sauve, Kalle Gehring
Summary: Parkinson's disease is a neurodegenerative disorder caused by the loss of dopaminergic neurons. Mutations in PRKN and PINK1 genes are responsible for early onset Parkinson's. Our research shows that PINK1 can activate PRKN to promote mitophagy. This signaling pathway offers potential for the development of therapeutics.
Article
Neurosciences
Isabella Russo, Luigi Bubacco, Elisa Greggio
Summary: This review summarizes the role of LRRK2 in modulating central and peripheral inflammation in Parkinson's disease and inflammatory disease models. In addition, it discusses the potential benefits of LRRK2 inhibitors and anti-inflammatory drugs in reducing disease risk and progression.
NEUROBIOLOGY OF DISEASE
(2022)
Article
Chemistry, Medicinal
Albert W. Garofalo, Jacob Schwarz, Kerry Zobel, Claudia Beato, Silvia Bernardi, Federica Budassi, Laura Caberlotto, Peng Gao, Cristiana Griffante, Xinying Liu, Marco Migliore, Feifei Qiao, Fabio Maria Sabbatini, Anna Sava, Mingliang Zhang, Holly J. Carlisle
Summary: The G2019S variant of LRRK2 is associated with Parkinson's disease (PD) and causes an increase in kinase activity. A series of novel kinase inhibitors have been discovered that selectively inhibit the phosphorylation of LRRK2 in the mouse brain, offering potential for precision medicine in future PD therapeutics.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Clinical Neurology
Ying Fan, Raja S. Nirujogi, Alicia Garrido, Javier Ruiz-Martinez, Alberto Bergareche-Yarza, Elisabet Mondragon-Rezola, Ana Vinagre-Aragon, Ioana Croitoru, Ana Gorostidi Pagola, Laura Paternain Markinez, Roy Alcalay, Richard A. Hickman, Jonas During, Sara Gomes, Neringa Pratuseviciute, Shalini Padmanabhan, Francesc Valldeoriola, Leticia Perez Sisques, Cristina Malagelada, Teresa Ximelis, Laura Molina Porcel, Maria Jose Marti, Eduardo Tolosa, Dario R. Alessi, Esther M. Sammler
Summary: This study found a significant increase in pRab10(Thr73) phosphorylation in carriers of the LRRK2 R1441G mutation, whereas the effect of the LRRK2 G2019S mutation was not statistically significant. Analysis of pRab10(Thr73) phosphorylation in post-mortem brain samples revealed high variability mainly due to the adverse effects of the peri- and post-mortem period on protein phosphorylation stability.
ACTA NEUROPATHOLOGICA
(2021)
Review
Chemistry, Medicinal
Jiarui Hu, Dan Zhang, Keyue Tian, Changyu Ren, Heng Li, Congcong Lin, Xiaoli Huang, Jie Liu, Wuyu Mao, Jifa Zhang
Summary: Leucine-rich repeat kinase 2 (LRRK2) is a multifunctional protein involved in various cellular processes and its hyperactivation leads to Parkinson's disease. Inhibiting LRRK2 is a promising therapeutic strategy for PD and recent studies have identified LRRK2 inhibitors with tissue specificity. Currently, there are four small-molecule LRRK2 inhibitors undergoing clinical trials. This review provides valuable information for the development of novel drugs targeting LRRK2.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
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
Biochemistry & Molecular Biology
Suzanne R. Pfeffer
Summary: Rab GTPases are critical regulators of secretory and endocytic pathways. Mutations in LRRK2 kinase lead to Parkinson's disease, and Rab GTPases are important substrates of LRRK2. Phosphorylation of Rab proteins by LRRK2 influences effector selection and has significant consequences for cell pathophysiology.
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.
Article
Clinical Neurology
Pei Wang, Peijing Cui, Qi Luo, Jie Chen, Huidong Tang, Lina Zhang, Shengdi Chen, Jianfang Ma
Summary: The penetrance of the G2385R variant in the Chinese population was found to be 25.9%.
EUROPEAN JOURNAL OF NEUROLOGY
(2022)
Article
Neurosciences
Susanna Cogo, Franz Y. Ho, Elena Tosoni, James E. Tomkins, Isabella Tessari, Lucia Iannotta, Thomas J. Montine, Claudia Manzoni, Patrick A. Lewis, Luigi Bubacco, Marie-Christine Chartier Harlin, Jean-Marc Taymans, Arjan Kortholt, Jeremy Nichols, Laura Cendron, Laura Civiero, Elisa Greggio
Summary: This article discusses the importance of Leucine-rich repeat kinase 2 (LRRK2) in Parkinson's disease (PD) research and its relationship with GTPase/Roc and kinase catalytic functions. The study found that Roc mutations can affect the activity of LRRK2 and discusses the molecular interactions between Roc and the regulation of cytoskeletal dynamics and intracellular trafficking pathways.
Article
Clinical Neurology
Dezhi Huang, Mingming Zhang, Zhigang Tan
Summary: Bone marrow mesenchymal stem cell-derived exosome (BMSCs-Exo)-derived TNF-stimulated gene-6 (TSG-6) has anti-inflammatory and antioxidative stress-related properties that may be beneficial in the treatment of Parkinson disease (PD) patients. BMSCs-Exo-derived TSG-6 attenuated neurotoxicity via the STAT3-miR-7-NEDD4 axis in an in vitro model of PD.
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
(2022)
Article
Biochemistry & Molecular Biology
Alexander Myasnikov, Hanwen Zhu, Patricia Hixson, Boer Xie, Kaiwen Yu, Aaron Pitre, Junmin Peng, Ji Sun
Summary: Mutations in LRRK2 are commonly associated with Parkinson's disease. This study provides insights into the physiological and pathological roles of LRRK2, and establishes a structural template for future therapeutic interventions in PD. The high-resolution structures of full-length human LRRK2 and COR-mediated LRRK2 dimers reveal key elements for rationalizing disease-causing mutations and potential targets for inhibitors.
Article
Biochemistry & Molecular Biology
Jun Ogata, Kentaro Hirao, Kenya Nishioka, Arisa Hayashida, Yuanzhe Li, Hiroyo Yoshino, Soichiro Shimizu, Nobutaka Hattori, Yuzuru Imai
Summary: A novel LRRK2 variant-p.G2294R located in the WD40 domain was detected in a patient with familial Parkinson's disease through targeted gene-panel screening. This variant was found to be highly destabilized at the protein level. Experimental results showed upregulated expression of the LRRK2 p.G2294R protein in the patient's peripheral blood lymphocytes, while macrophages differentiated from the same blood sample exhibited decreased levels of LRRK2 protein. Additionally, reduced phagocytic activity was observed in pathogenic yeasts and alpha-synuclein fibrils.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Elena Fdez, Jesus Madero-Perez, Antonio J. Lara Ordonez, Yahaira Naaldijk, Rachel Fasiczka, Ana Aiastui, Javier Ruiz-Martinez, Adolfo Lopez de Munain, Sally A. Cowley, Richard Wade-Martins, Sabine Hilfiker
Summary: Mutations in LRRK2 gene increase its kinase activity, leading to Parkinson's disease. LRRK2 phosphorylates a subset of Rab proteins, resulting in their binding to RILPL1 and causing deficits in ciliogenesis and centrosome cohesion. The study demonstrates that centrosomal deficits caused by pathogenic LRRK2 can be observed in patient-derived iPS cells, and the underlying mechanism has been identified using transiently transfected cell lines. The LRRK2-mediated centrosomal cohesion deficits depend on both the GTP conformation and phosphorylation status of Rab proteins.
Article
Cell Biology
Joanne Toh, Ling Ling Chua, Patrick Ho, Edwin Sandanaraj, Carol Tang, Hongyan Wang, Eng King Tan
Summary: This study demonstrates the neuroprotective effects of LRRK2 protective variants in a Parkinson's disease fruit fly model. RNA sequencing revealed upregulation of specific gene pathways in flies carrying the pathogenic variant, which was restored in rescue phenotypes. Using protective gene variants may offer potential new therapeutic targets for aging and neurodegeneration in PD.
Article
Chemistry, Organic
Sviatoslav S. Eliseenko, Fei Liu
Article
Biochemistry & Molecular Biology
Michael P. Gotsbacher, Sung Min Cho, Nam Hee Kim, Fei Liu, Ho Jeong Kwon, Peter Karuso
ACS CHEMICAL BIOLOGY
(2019)
Article
Biochemical Research Methods
Ari Hardianto, Varun Khanna, Fei Liu, Shoba Ranganathan
BMC BIOINFORMATICS
(2019)
Article
Multidisciplinary Sciences
Matthew Ku, Ruth N. MacKinnon, Meaghan Wall, Nisha Narayan, Carl Walkley, Heung-Chin Cheng, Lynda J. Campbell, Louise E. Purton, Harshal Nandurkar
SCIENTIFIC REPORTS
(2019)
Article
Biotechnology & Applied Microbiology
Payal Barua, Seong Beom Ahn, Abidali Mohamedali, Fei Liu
BIOTECHNOLOGY LETTERS
(2020)
Article
Biochemistry & Molecular Biology
Riley D. Metcalfe, Kaheina Aizel, Courtney O. Zlatic, Paul M. Nguyen, Craig J. Morton, Daisy Sio-Seng Lio, Heung-Chin Cheng, Renwick C. J. Dobson, Michael W. Parker, Paul R. Gooley, Tracy L. Putoczki, Michael D. W. Griffin
JOURNAL OF BIOLOGICAL CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Sviatoslav S. Eliseenko, Mohan Bhadbhade, Fei Liu
Article
Biochemistry & Molecular Biology
Jerran Santos, Sibasish Dolai, Matthew B. O'Rourke, Fei Liu, Matthew P. Padula, Mark P. Molloy, Bruce K. Milthorpe
Summary: The differentiation of human adipose derived stem cells towards a neural phenotype using small molecules has been a popular research topic, and proteomic profiling has revealed the changes in enriched proteins at different timepoints. These unique proteins identified play critical roles in neurogenic differentiation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Organic
Ryan T. Kenny, Fei Liu
Summary: A robust synthesis of Soai-type pyrimidine aldehydes was achieved by controlled formation and quenching of a lithiated pyrimidine intermediate. The optimized rate of n-BuLi addition synchronized with the addition to ethyl formate, resulting in consistently high yields of 2-alkylpyrimidinecarboxaldehydes, which can be used in autocatalysis or as functionalized synthons.
ASIAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Jinling Liu, Yinghua Yu, Xueliang Huang
Summary: Deuterated compounds are important in pharmaceutical chemistry and the selective incorporation of deuterium atoms onto pharmacophore-containing compounds is of great interest. In this study, a concise method for constructing deuterated dibenzo-fused epsilon-lactones and epsilon-lactams through Pd-catalyzed carbene bridging C-D bond activation strategy was described. Deuterated ortho-bromobenzaldehydes were readily available reactants and deuterium atoms were selectively incorporated at the dibenylic position with high deuterated ratio.
ASIAN JOURNAL OF ORGANIC CHEMISTRY
(2022)
Review
Oncology
Rajdeep Chakraborty, Charbel Darido, Fei Liu, Maciej Maselko, Shoba Ranganathan
Summary: Immune therapies have shown promising results in the treatment of head and neck cancer by boosting the patient's immune system to fight tumor spread. This review highlights recent clinical success in the field of head and neck cancer immunotherapy, including the development of immune checkpoint inhibitors and a human papilloma virus vaccine. The review also emphasizes the importance of understanding basic biology and implementing personalized immunotherapy for better treatment outcomes.
Article
Multidisciplinary Sciences
Rajdeep Chakraborty, Charbel Darido, Arthur Chien, Aidan Tay, Karen Vickery, Honghua Hu, Fei Liu, Shoba Ranganathan
Summary: The role of Gipie in adenoid cystic carcinoma (ACC) and mucoepidermoid carcinoma (A-253) was evaluated in this study. Results showed that silencing Gipie led to morphological changes in the cells, increased apoptosis, decreased T regulatory cells, and increased activated NK cells.
SCIENTIFIC REPORTS
(2023)
Article
Chemistry, Medicinal
Ivan de Jesus Salazar-Estrada, Karthik Shantharam Kamath, Fei Liu
Summary: The SADL approach utilizes two covalent modifiers under a common ligand directive for precise protein labeling, improving target selectivity and labeling precision, broadening protein identification opportunities, aiding in understanding biological or disease mechanisms, and accelerating drug target discovery.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)
Article
Biochemical Research Methods
Michael G. Leeming, Sean O'Callaghan, Luana Licata, Marta Iannuccelli, Prisca Lo Surdo, Elisa Micarelli, Ching-Seng Ang, Shuai Nie, Swati Varshney, Sadia Ameen, Heung-Chin Cheng, Nicholas A. Williamson
Summary: Phosphomatics is a publicly available web resource for investigating phosphoproteomics data and allows researchers to explore relationships of phosphorylation sites from different perspectives. Researchers can upload and analyze phosphoproteomics data through Phosphomatics to identify possible upstream kinases and pathways for further study.
Review
Biochemistry & Molecular Biology
Miaomiao Liu, Peter Karuso, Yunjiang Feng, Esther Kellenberger, Fei Liu, Can Wang, Ronald J. Quinn