دورية أكاديمية
LRRK2 exonic variants are associated with lysosomal hydrolase activities and lysosphingolipid alterations in Parkinson's disease.
| العنوان: | LRRK2 exonic variants are associated with lysosomal hydrolase activities and lysosphingolipid alterations in Parkinson's disease. |
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| المؤلفون: | Usenko TS; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia. Electronic address: usenko_ts@pnpi.nrcki.ru., Senkevich KA; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia; The Neuro (Montreal Neurological Institute-Hospital), McGill University, Montreal, QC, Canada; Department of Neurology and neurosurgery, McGill University, Montréal, QC, Canada., Basharova KS; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia., Bezrukova AI; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia., Baydakova GV; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia; Research Center for Medical Genetics, Moscow, Russia., Tyurin AA; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia., Beletskaya MV; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia., Kulabukhova DG; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia., Grunina MN; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia., Emelyanov AK; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia., Miliukhina IV; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia; Institute of the Human Brain of RAS, Saint-Petersburg, Russia., Timofeeva AA; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia., Zakharova EY; Research Center for Medical Genetics, Moscow, Russia., Pchelina SN; Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», Gatchina, Russia; Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg, Russia. |
| المصدر: | Gene [Gene] 2023 Oct 05; Vol. 882, pp. 147639. Date of Electronic Publication: 2023 Jul 18. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier/North-Holland Country of Publication: Netherlands NLM ID: 7706761 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-0038 (Electronic) Linking ISSN: 03781119 NLM ISO Abbreviation: Gene Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Amsterdam, Elsevier/North-Holland, 1976- |
| مواضيع طبية MeSH: | Parkinson Disease*/genetics, Humans ; Glucosylceramidase/genetics ; Glucosylceramidase/metabolism ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Mutation ; Sphingolipids ; Lysosomes |
| مستخلص: | Last data demonstrated that exonic variants of LRRK2 (p.G2019S, p.M1646T) may affect the catalytic activity of lysosomal enzyme glucocerebrosidase (GCase) probably through the phosphorylation of Rab10 protein. We aimed to evaluate an association of LRRK2 exonic variants previously associated with alteration of phosphorylation levels for Rab10 Thr73 with PD risk in Russian population and analyze an impact of p.G2019S mutation and selected LRRK2 variants on lysosomal hydrolase activities. LRRK2 variants were determined by full sequencing of LRRK2 in 508 PD patients and 470 controls from Russian population. Activity of lysosomal enzymes (glucocerebrosidase (GCase), alpha-galactosidase A (GLA), acid sphingomyelinase (ASMase) and concentrations of their corresponded substrates (hexosylsphingosine (HexSph), globotriaosylsphingosine (LysoGb3), lysosphingomyelin (LysoSM), respectively) were estimated in 211 PD patients and 179 controls by liquid chromatography with tandem mass spectrometry (LC-MS-MS) in dry blood spots. p.M1646T and p.N2081D were associated with PD (OR = 2.33, CI 95%: 1.1215 to 4.8253, p = 0.023; OR = 1.89, 95%CI: 1.0727 to 3.3313, p = 0.028, respectively) in Russian population. An increased LysoGb3 concentration was found in p.G2019S and p.N2081D LRRK2 carriers among PD patients compared to both PD patients and controls (p.G2019S: p = 0.00086, p = 0.0004, respectively; p.N2081D: p = 0.012, p = 0.0076, respectively). A decreased ASMase activity in p.G2019S LRRK2 carriers among PD patients (p = 0.014) was demonstrated as well. Our study supported possible involvement of LRRK2 dysfunction in an alteration of sphingolipid metabolism in PD. Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2023 Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: Blood; LRRK2; Lysosomal enzymes; Parkinson’s disease; Sphingolipids |
| المشرفين على المادة: | EC 3.2.1.45 (Glucosylceramidase) EC 2.7.11.1 (Leucine-Rich Repeat Serine-Threonine Protein Kinase-2) 0 (Sphingolipids) EC 2.7.11.1 (LRRK2 protein, human) |
| تواريخ الأحداث: | Date Created: 20230720 Date Completed: 20230811 Latest Revision: 20230811 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.gene.2023.147639 |
| PMID: | 37473971 |
| قاعدة البيانات: | MEDLINE |
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