Alterations in the LRRK2-Rab pathway in ...
Document type :
Article dans une revue scientifique: Article original
PMID :
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Title :
Alterations in the LRRK2-Rab pathway in urinary extracellular vesicles as Parkinson's disease and pharmacodynamic biomarkers.
Author(s) :
Taymans, Jean-Marc [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Mutez, Eugenie [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Sibran, William [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Vandewynckel, Laurine [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Deldycke, Claire [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Bleuse, Séverine [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Marchand, Antoine [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Sarchione, Alessia [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Leghay, Coline [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Kreisler, Alexandre [Auteur]
Service de neurologie et pathologie du mouvement
Simonin, Clemence [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Koprich, J. [Auteur]
Baille, Guillaume [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Defebvre, Luc [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Dujardin, Kathy [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Destée, Alain [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Chartier-Harlin, Marie-Christine [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Lille Neurosciences & Cognition (LilNCog) - U 1172
Mutez, Eugenie [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Sibran, William [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Vandewynckel, Laurine [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Deldycke, Claire [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Bleuse, Séverine [Auteur]
Centre Hospitalier Régional Universitaire [CHU Lille] [CHRU Lille]
Marchand, Antoine [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Sarchione, Alessia [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Leghay, Coline [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Kreisler, Alexandre [Auteur]
Service de neurologie et pathologie du mouvement
Simonin, Clemence [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Koprich, J. [Auteur]
Baille, Guillaume [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Defebvre, Luc [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Dujardin, Kathy [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Destée, Alain [Auteur]
Lille Neurosciences & Cognition - U 1172 [LilNCog]
Chartier-Harlin, Marie-Christine [Auteur]
Lille Neurosciences & Cognition (LilNCog) - U 1172
Journal title :
NPJ Parkinsons Dis
Volume number :
9
Publisher :
Springer Nature
Publication date :
2023-02-09
ISSN :
2373-8057
HAL domain(s) :
Sciences du Vivant [q-bio]
English abstract : [en]
Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess ...
Show more >Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess the LRRK2-Rab pathway for use as biomarkers in human, non-human primate (NHP) and rat urine. With urine collected from human subjects and animals, we applied an ultracentrifugation based fractionation protocol to isolate small urinary extracellular vesicles (uEVs). We used western blot with antibodies directed against total and phosphorylated LRRK2, Rab8, and Rab10 to measure these LRRK2 and Rab epitopes in uEVs. We confirm the presence of LRRK2 and Rab8/10 in human and NHP uEVs, including total LRRK2 as well as phospho-LRRK2, phospho-Rab8 and phospho-Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, without significant differences between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to increased Rab8 levels and decreased pS910-LRRK2 and pS935-LRRK2. In animals, acute treatment with LRRK2 kinase inhibitors led to decreased pT73-Rab10. The identification of changes in Rab8 and LRRK2 phosphorylation at S910 and S935 heterologous phosphosites in uEVs of PD patients and pT73-Rab10 in inhibitor-dosed animals further reinforces the potential of the LRRK2-Rab pathway as a source of PD and pharmacodynamic biomarkers in uEVs.Show less >
Show more >Expression or phosphorylation levels of leucine-rich repeat kinase 2 (LRRK2) and its Rab substrates have strong potential as disease or pharmacodynamic biomarkers. The main objective of this study is therefore to assess the LRRK2-Rab pathway for use as biomarkers in human, non-human primate (NHP) and rat urine. With urine collected from human subjects and animals, we applied an ultracentrifugation based fractionation protocol to isolate small urinary extracellular vesicles (uEVs). We used western blot with antibodies directed against total and phosphorylated LRRK2, Rab8, and Rab10 to measure these LRRK2 and Rab epitopes in uEVs. We confirm the presence of LRRK2 and Rab8/10 in human and NHP uEVs, including total LRRK2 as well as phospho-LRRK2, phospho-Rab8 and phospho-Rab10. We also confirm LRRK2 and Rab expression in rodent uEVs. We quantified LRRK2 and Rab epitopes in human cohorts and found in a first cohort that pS1292-LRRK2 levels were elevated in individuals carrying the LRRK2 G2019S mutation, without significant differences between healthy and PD groups, whether for LRRK2 G2019S carriers or not. In a second cohort, we found that PD was associated to increased Rab8 levels and decreased pS910-LRRK2 and pS935-LRRK2. In animals, acute treatment with LRRK2 kinase inhibitors led to decreased pT73-Rab10. The identification of changes in Rab8 and LRRK2 phosphorylation at S910 and S935 heterologous phosphosites in uEVs of PD patients and pT73-Rab10 in inhibitor-dosed animals further reinforces the potential of the LRRK2-Rab pathway as a source of PD and pharmacodynamic biomarkers in uEVs.Show less >
Language :
Anglais
Audience :
Internationale
Popular science :
Non
Administrative institution(s) :
Université de Lille
Inserm
CHU Lille
Inserm
CHU Lille
Collections :
Submission date :
2024-01-15T23:47:57Z
2024-09-18T10:06:59Z
2024-09-18T10:06:59Z
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