Interrogating Parkinson's disease LRRK2 kinase pathway activity by assessing Rab10 phosphorylation in human neutrophils
Autor: | Ying, Fan, Andrew J M, Howden, Adil R, Sarhan, Pawel, Lis, Genta, Ito, Terina N, Martinez, Kathrin, Brockmann, Thomas, Gasser, Dario R, Alessi, Esther M, Sammler |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
pharmacology [Protein Kinase Inhibitors]
pathology [Leukocytes Mononuclear] antagonists & inhibitors [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] Parkinson's disease Epitopes neutrophils Antibody Specificity genetics [Parkinson Disease] immunology [Gyrus Cinguli] diagnostics antibodies Phosphorylation Research Articles Clinical Trials as Topic immunology [Neutrophils] pathology [Neutrophils] isolation & purification [Antibodies Phospho-Specific] Antibodies Monoclonal Parkinson Disease LRRK2 immunology [Epitopes] ddc:540 Rabbits Rab10 protein human Signal Transduction Research Article monoclonal Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Gyrus Cinguli immunology [Parkinson Disease] leucine-rich repeat kinase immunology [Leukocytes Mononuclear] Commentaries chemistry [Epitopes] immunology [rab GTP-Binding Proteins] Animals Humans chemistry [Antibodies Monoclonal] Genetic Predisposition to Disease chemistry [rab GTP-Binding Proteins] LRRK2 protein human chemistry [Antibodies Phospho-Specific] Protein Kinase Inhibitors physiopathology [Gyrus Cinguli] Enzyme Assays biomarkers nervous system diseases immunology [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] Gene Expression Regulation Rab proteins rab GTP-Binding Proteins Case-Control Studies Mutation Rab10 Leukocytes Mononuclear Commentary genetics [Leucine-Rich Repeat Serine-Threonine Protein Kinase-2] genetics [rab GTP-Binding Proteins] enzymology [Parkinson Disease] Antibodies Phospho-Specific isolation & purification [Antibodies Monoclonal] |
Zdroj: | Biochemical Journal Biochemical journal 475(1), 23-44 (2017). doi:10.1042/BCJ20170803 |
ISSN: | 1470-8728 0264-6021 |
DOI: | 10.1042/BCJ20170803 |
Popis: | The addition of phosphate groups to substrates allows protein kinases to regulate a myriad of biological processes, and contextual analysis of protein-bound phosphate is important for understanding how kinases contribute to physiology and disease. Leucine-rich repeat kinase 2 (LRRK2) is a Ser/Thr kinase linked to familial and sporadic cases of Parkinson's disease (PD). Recent work established that multiple Rab GTPases are physiological substrates of LRRK2, with Rab10 in particular emerging as a human substrate whose site-specific phosphorylation mirrors hyperactive LRRK2 lesions associated with PD. However, current assays to quantify Rab10 phosphorylation are expensive, time-consuming and technically challenging. In back-to-back studies reported in the Biochemical Journal, Alessi and colleagues teamed up with clinical colleagues and collaborators at the Michael J. Fox Foundation (MJFF) for Parkinson's research to develop, and validate, a panel of exquisitely sensitive phospho-specific Rab antibodies. Of particular interest, the monoclonal antibody-designated MJFF-pRAB10 detects phosphorylated Rab 10 on Thr73 in a variety of cells, brain extracts, PD-derived samples and human neutrophils, the latter representing a previously unrecognised biological resource for LRRK2 signalling analysis. In the future, these antibodies could become universal resources in the fight to understand and quantify connections between LRRK2 and Rab proteins, including those associated with clinical PD. |
Databáze: | OpenAIRE |
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