Détail du document
Identifiant

oai:pubmedcentral.nih.gov:8248...

Sujet
Regular Issue Articles
Auteur
Bright, Jessica M. Carlisle, Holly J. Toda, Alyssa M. A. Murphy, Molly Molitor, Tyler P. Wren, Paul Andruska, Kristin M. Liu, Enchi Barlow, Carrolee
Langue
en
Editeur

John Wiley & Sons, Inc.

Catégorie

Wiley-Blackwell Online Open

Année

2021

Date de référencement

01/12/2023

Mots clés
eb‐42168 wt kinase mutation pser935 patients parkinson g2019s lrrk2
Métrique

Résumé

BACKGROUND: A common genetic mutation that causes Parkinson's disease (PD) is the G2019S LRRK2 mutation.

A precision medicine approach that selectively blocks only excess kinase activity of the mutant allele could yield a safe and effective treatment for G2019S LRRK2 PD.

OBJECTIVE: To determine the activity of a G2019S mutant selective leucine‐rich repeat kinase 2 (LRRK2) kinase inhibitor as compared to a nonselective inhibitor in blood of subjects with genetic and idiopathic PD on two LRRK2 biomarkers, pSer935 LRRK2 and pThr73 Rab10.

METHODS: Blood was collected from 13 subjects with or without a G2019S LRRK2 mutation with PD and one healthy control.

Peripheral blood mononuclear cells were treated ex vivo with a novel G2019S LRRK2 inhibitor (EB‐42168) or the nonselective inhibitor MLi‐2.

Quantitative western immunoblot analyses were performed.

RESULTS: EB‐42168 was 100 times more selective for G2019S LRRK2 when compared to wild‐type (WT) LRRK2.

Concentrations that inhibited phosphorylation of pSer935 LRRK2 by 90% in homozygous G2019S LRRK2 patients, inhibited pSer935 LRRK2 by 36% in heterozygous patients, and by only 5% in patients carrying only the WT allele.

Similar selectivity was seen for pThr73 Rab10.

MLi‐2 showed an equivalent level of inhibition across all genotypes.

CONCLUSIONS: These findings demonstrate that EB‐42168, a G2019S LRRK2 selective inhibitor, lowers mutant G2019S LRRK2 phosphorylated biomarkers while simultaneously sparing WT LRRK2.

Selective targeting of G2019S LRRK2 with a small molecule lays the foundation for a precision medicine treatment of G2019S LRRK2 PD.

© 2021 ESCAPE Bio, Inc.

Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Bright, Jessica M.,Carlisle, Holly J.,Toda, Alyssa M. A.,Murphy, Molly,Molitor, Tyler P.,Wren, Paul,Andruska, Kristin M.,Liu, Enchi,Barlow, Carrolee, 2021, Differential Inhibition of LRRK2 in Parkinson's Disease Patient Blood by a G2019S Selective LRRK2 Inhibitor, John Wiley & Sons, Inc.

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