Cargando…
Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease
BACKGROUND: Pathogenic leucine‐rich repeat kinase 2 LRRK2 mutations may increase LRRK2 kinase activity and Rab substrate phosphorylation. Genetic association studies link variation in LRRK2 to idiopathic Parkinson disease (iPD) risk. OBJECTIVES: Through measurements of the LRRK2 kinase substrate pT7...
Autores principales: | , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley & Sons, Inc.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308673/ https://www.ncbi.nlm.nih.gov/pubmed/35521944 http://dx.doi.org/10.1002/mds.29043 |
_version_ | 1784753021687693312 |
---|---|
author | Wang, Shijie Unnithan, Shakthi Bryant, Nicole Chang, Allison Rosenthal, Liana S. Pantelyat, Alexander Dawson, Ted M. Al‐Khalidi, Hussein R. West, Andrew B. |
author_facet | Wang, Shijie Unnithan, Shakthi Bryant, Nicole Chang, Allison Rosenthal, Liana S. Pantelyat, Alexander Dawson, Ted M. Al‐Khalidi, Hussein R. West, Andrew B. |
author_sort | Wang, Shijie |
collection | PubMed |
description | BACKGROUND: Pathogenic leucine‐rich repeat kinase 2 LRRK2 mutations may increase LRRK2 kinase activity and Rab substrate phosphorylation. Genetic association studies link variation in LRRK2 to idiopathic Parkinson disease (iPD) risk. OBJECTIVES: Through measurements of the LRRK2 kinase substrate pT73‐Rab10 in urinary extracellular vesicles, this study seeks to understand how LRRK2 kinase activity might change with iPD progression. METHODS: Using an immunoblotting approach validated in LRRK2 transgenic mice, the ratio of pT73‐Rab10 to total Rab10 protein was measured in extracellular vesicles from a cross‐section of G2019S LRRK2 mutation carriers (N = 45 participants) as well as 485 urine samples from a novel longitudinal cohort of iPD and controls (N = 85 participants). Generalized estimating equations were used to conduct analyses with commonly used clinical scales. RESULTS: Although the G2019S LRRK2 mutation did not increase pT73‐Rab10 levels, the ratio of pT73‐Rab10 to total Rab10 nominally increased over baseline in iPD urine vesicle samples with time, but did not increase in age‐matched controls (1.34‐fold vs. 1.05‐fold, 95% confidence interval [CI], 0.004–0.56; P = 0.046; Welch's t test). Effect estimates adjusting for sex, age, disease duration, diagnosis, and baseline clinical scores identified increasing total Movement Disorder Society‐Sponsored Revision of the Unified (MDS‐UPDRS) scores (β = 0.77; CI, 0.52–1.01; P = 0.0001) with each fold increase of pT73‐Rab10 to total Rab10. Lower Montreal Cognitive Assessment (MoCA) score in iPD is also associated with increased pT73‐Rab10. CONCLUSIONS: These results provide initial insights into peripheral LRRK2‐dependent Rab phosphorylation, measured in biobanked urine, where higher levels of pT73‐Rab10 are associated with worse disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. |
format | Online Article Text |
id | pubmed-9308673 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley & Sons, Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-93086732022-10-14 Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease Wang, Shijie Unnithan, Shakthi Bryant, Nicole Chang, Allison Rosenthal, Liana S. Pantelyat, Alexander Dawson, Ted M. Al‐Khalidi, Hussein R. West, Andrew B. Mov Disord Regular Issue Articles BACKGROUND: Pathogenic leucine‐rich repeat kinase 2 LRRK2 mutations may increase LRRK2 kinase activity and Rab substrate phosphorylation. Genetic association studies link variation in LRRK2 to idiopathic Parkinson disease (iPD) risk. OBJECTIVES: Through measurements of the LRRK2 kinase substrate pT73‐Rab10 in urinary extracellular vesicles, this study seeks to understand how LRRK2 kinase activity might change with iPD progression. METHODS: Using an immunoblotting approach validated in LRRK2 transgenic mice, the ratio of pT73‐Rab10 to total Rab10 protein was measured in extracellular vesicles from a cross‐section of G2019S LRRK2 mutation carriers (N = 45 participants) as well as 485 urine samples from a novel longitudinal cohort of iPD and controls (N = 85 participants). Generalized estimating equations were used to conduct analyses with commonly used clinical scales. RESULTS: Although the G2019S LRRK2 mutation did not increase pT73‐Rab10 levels, the ratio of pT73‐Rab10 to total Rab10 nominally increased over baseline in iPD urine vesicle samples with time, but did not increase in age‐matched controls (1.34‐fold vs. 1.05‐fold, 95% confidence interval [CI], 0.004–0.56; P = 0.046; Welch's t test). Effect estimates adjusting for sex, age, disease duration, diagnosis, and baseline clinical scores identified increasing total Movement Disorder Society‐Sponsored Revision of the Unified (MDS‐UPDRS) scores (β = 0.77; CI, 0.52–1.01; P = 0.0001) with each fold increase of pT73‐Rab10 to total Rab10. Lower Montreal Cognitive Assessment (MoCA) score in iPD is also associated with increased pT73‐Rab10. CONCLUSIONS: These results provide initial insights into peripheral LRRK2‐dependent Rab phosphorylation, measured in biobanked urine, where higher levels of pT73‐Rab10 are associated with worse disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. John Wiley & Sons, Inc. 2022-05-06 2022-07 /pmc/articles/PMC9308673/ /pubmed/35521944 http://dx.doi.org/10.1002/mds.29043 Text en © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Regular Issue Articles Wang, Shijie Unnithan, Shakthi Bryant, Nicole Chang, Allison Rosenthal, Liana S. Pantelyat, Alexander Dawson, Ted M. Al‐Khalidi, Hussein R. West, Andrew B. Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease |
title | Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease |
title_full | Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease |
title_fullStr | Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease |
title_full_unstemmed | Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease |
title_short | Elevated Urinary Rab10 Phosphorylation in Idiopathic Parkinson Disease |
title_sort | elevated urinary rab10 phosphorylation in idiopathic parkinson disease |
topic | Regular Issue Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9308673/ https://www.ncbi.nlm.nih.gov/pubmed/35521944 http://dx.doi.org/10.1002/mds.29043 |
work_keys_str_mv | AT wangshijie elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT unnithanshakthi elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT bryantnicole elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT changallison elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT rosenthallianas elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT pantelyatalexander elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT dawsontedm elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT alkhalidihusseinr elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease AT westandrewb elevatedurinaryrab10phosphorylationinidiopathicparkinsondisease |