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
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