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LRRK2‐mediated Rab10 phosphorylation in immune cells from Parkinson's disease patients
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Personen und Körperschaften: | , , , , , , , , , |
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Titel: |
LRRK2‐mediated Rab10 phosphorylation in immune cells from Parkinson's disease patients |
In: | Movement Disorders, 34, 2019, 3, S. 406-415 |
veröffentlicht: |
Wiley
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Umfang: | 406-415 |
ISSN: |
0885-3185 1531-8257 |
DOI: | 10.1002/mds.27601 |
Zusammenfassung: | <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Leucine‐rich repeat kinase 2 is a potential therapeutic target for the treatment of Parkinson's disease, and clinical trials of leucine‐rich repeat kinase 2 inhibitors are in development. The objective of this study was to evaluate phosphorylation of a new leucine‐rich repeat kinase 2 substrate, Rab10, for potential use as a target engagement biomarker and/or patient enrichment biomarker for leucine‐rich repeat kinase 2 inhibitor clinical trials.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Peripheral blood mononuclear cells and neutrophils were isolated from Parkinson's disease patients and matched controls, and treated <jats:italic>ex vivo</jats:italic> with a leucine‐rich repeat kinase 2 inhibitor. Immunoblotting was used to measure levels of leucine‐rich repeat kinase 2 and Rab10 and their phosphorylation. Plasma inflammatory cytokines were measured by multiplex enzyme‐linked immunosorbent assay.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Mononuclear cells and neutrophils of both controls and Parkinson's disease patients responded the same to leucine‐rich repeat kinase 2 inhibitor treatment. Leucine‐rich repeat kinase 2 levels in mononuclear cells were the same in controls and Parkinson's disease patients, whereas leucine‐rich repeat kinase 2 was significantly increased in Parkinson's disease neutrophils. Rab10 T73 phosphorylation levels were similar in controls and Parkinson's disease patients and did not correlate with leucine‐rich repeat kinase 2 levels. Immune‐cell levels of leucine‐rich repeat kinase 2 and Rab10 T73 phosphorylation were associated with plasma inflammatory cytokine levels.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Rab10 T73 phosphorylation appears to be a valid target engagement biomarker for potential use in leucine‐rich repeat kinase 2 inhibitor clinical trials. However, a lack of association between leucine‐rich repeat kinase 2 and Rab10 phosphorylation complicates the potential use of Rab10 phosphorylation as a patient enrichment biomarker. Although replication is required, increased leucine‐rich repeat kinase 2 levels in neutrophils from Parkinson's disease patients may have the potential for patient stratification. leucine‐rich repeat kinase 2 activity in peripheral immune cells may contribute to an inflammatory phenotype. © 2018 International Parkinson and Movement Disorder Society</jats:p></jats:sec> |
Format: | E-Article |
Quelle: | Wiley (CrossRef) |
Sprache: | Englisch |