Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients.

Case-Control Studies Cell Line Cell Self Renewal / genetics Cell Survival / genetics Genetic Predisposition to Disease Humans Induced Pluripotent Stem Cells Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics Neural Stem Cells Parkinson Disease / genetics Phenotype Racemases and Epimerases / genetics Serine / metabolism
Genetic background LRRK2-G2019S Neuroepithelial stem cells Parkinson's disease Second hit Serine racemase Susceptibility factor

Journal

Parkinsonism & related disorders
ISSN: 1873-5126
Titre abrégé: Parkinsonism Relat Disord
Pays: England
ID NLM: 9513583

Informations de publication

Date de publication:
10 2019
Historique:
received: 14 06 2019
revised: 14 08 2019
accepted: 15 09 2019
pubmed: 18 10 2019
medline: 25 8 2020
entrez: 18 10 2019
Statut: ppublish

Résumé

Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD. To assess LRRK2-G2019S modifiers, we used human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal and viability, as well as impaired serine metabolism. In patient cells, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. In this context we identified the gene serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the aberrant phenotypes. Its enzymatic product, d-serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.

Identifiants

DOI: 10.1016/j.parkreldis.2019.09.018 PMID: 31621607
pubmed: 31621607
pii: S1353-8020(19)30395-5
doi: 10.1016/j.parkreldis.2019.09.018
pii:
doi:

Substances chimiques

Serine 452VLY9402
LRRK2 protein, human EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 EC 2.7.11.1
Racemases and Epimerases EC 5.1.-
serine racemase EC 5.1.1.16

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

48-55

Informations de copyright

Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Auteurs

Sarah Louise Nickels (SL)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg; Life Sciences Research Unit (LSRU), Systems Biology Group, University of Luxembourg, L-4367, Belvaux, Luxembourg; Integrated Biobank of Luxembourg (IBBL), Luxembourg Institute of Health, L-3555, Dudelange, Luxembourg.

Jonas Walter (J)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Silvia Bolognin (S)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Deborah Gérard (D)

Life Sciences Research Unit (LSRU), Systems Biology Group, University of Luxembourg, L-4367, Belvaux, Luxembourg.

Christian Jaeger (C)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Xiaobing Qing (X)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Johan Tisserand (J)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Javier Jarazo (J)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Kathrin Hemmer (K)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Amy Harms (A)

Leiden Academic Centre for Drug Research (LACDR), Analytical Biosciences, Leiden University, NL-2333, CC Leiden, Netherlands.

Rashi Halder (R)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Philippe Lucarelli (P)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Emanuel Berger (E)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Paul M A Antony (PMA)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Enrico Glaab (E)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg.

Thomas Hankemeier (T)

Leiden Academic Centre for Drug Research (LACDR), Analytical Biosciences, Leiden University, NL-2333, CC Leiden, Netherlands.

Christine Klein (C)

Institute of Neurogenetics, University of Lübeck, D-23538, Lübeck, Germany.

Thomas Sauter (T)

Life Sciences Research Unit (LSRU), Systems Biology Group, University of Luxembourg, L-4367, Belvaux, Luxembourg.

Lasse Sinkkonen (L)

Life Sciences Research Unit (LSRU), Systems Biology Group, University of Luxembourg, L-4367, Belvaux, Luxembourg.

Jens Christian Schwamborn (JC)

Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, L-4367, Belvaux, Luxembourg. Electronic address: jens.schwamborn@uni.lu.

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Classifications MeSH

questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études cas-témoins › Impaired serine metabolism complements...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Impaired serine metabolism complements...
questionsmedicales.fr › Phénomènes physiologiques › Croissance et développement › Croissance › Processus de croissance cellulaire › Prolifération cellulaire › Division cellulaire › Auto-renouvellement cellulaire › Impaired serine metabolism complements...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Survie cellulaire › Impaired serine metabolism complements...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Prédisposition génétique à une maladie › Impaired serine metabolism complements...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Impaired serine metabolism complements...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches pluripotentes › Cellules souches pluripotentes induites › Impaired serine metabolism complements...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines associées à la maladie de Parkinson › Leucine-rich repeat serine-threonine protein kinase-2 › Impaired serine metabolism complements...
questionsmedicales.fr › Cellules › Cellules souches › Cellules souches neurales › Impaired serine metabolism complements...
questionsmedicales.fr › Maladies du système nerveux › Maladies neurodégénératives › Maladie de Parkinson › Impaired serine metabolism complements...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Impaired serine metabolism complements...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Isomerases › Racémases et épimérases › Impaired serine metabolism complements...
questionsmedicales.fr › Acides aminés, peptides et protéines › Acides aminés › Acides aminés neutres › Sérine › Impaired serine metabolism complements...