Induced pluripotent stem cell-based modeling of mutant LRRK2-associated Parkinson's disease.
LRRK2
Parkinson's disease
disease modeling
iPSC
mitophagy
Journal
The European journal of neuroscience
ISSN: 1460-9568
Titre abrégé: Eur J Neurosci
Pays: France
ID NLM: 8918110
Informations de publication
Date de publication:
02 2019
02 2019
Historique:
received:
19
06
2018
revised:
13
12
2018
accepted:
10
01
2019
pubmed:
19
1
2019
medline:
23
6
2020
entrez:
19
1
2019
Statut:
ppublish
Résumé
Recent advances in cell reprogramming have enabled assessment of disease-related cellular traits in patient-derived somatic cells, thus providing a versatile platform for disease modeling and drug development. Given the limited access to vital human brain cells, this technology is especially relevant for neurodegenerative disorders such as Parkinson's disease (PD) as a tool to decipher underlying pathomechanisms. Importantly, recent progress in genome-editing technologies has provided an ability to analyze isogenic induced pluripotent stem cell (iPSC) pairs that differ only in a single genetic change, thus allowing a thorough assessment of the molecular and cellular phenotypes that result from monogenetic risk factors. In this review, we summarize the current state of iPSC-based modeling of PD with a focus on leucine-rich repeat kinase 2 (LRRK2), one of the most prominent monogenetic risk factors for PD linked to both familial and idiopathic forms. The LRRK2 protein is a primarily cytosolic multi-domain protein contributing to regulation of several pathways including autophagy, mitochondrial function, vesicle transport, nuclear architecture and cell morphology. We summarize iPSC-based studies that contributed to improving our understanding of the function of LRRK2 and its variants in the context of PD etiopathology. These data, along with results obtained in our own studies, underscore the multifaceted role of LRRK2 in regulating cellular homeostasis on several levels, including proteostasis, mitochondrial dynamics and regulation of the cytoskeleton. Finally, we expound advantages and limitations of reprogramming technologies for disease modeling and drug development and provide an outlook on future challenges and expectations offered by this exciting technology.
Identifiants
pubmed: 30656775
doi: 10.1111/ejn.14345
pmc: PMC7114274
doi:
Substances chimiques
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
561-589Subventions
Organisme : European Union
ID : FP7-HEALTH-F4-2013-602278-Neurostemcellrepair
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : BL 767/3-1
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : BL 767/4-1
Pays : International
Organisme : German Ministry for Education and Research (BMBF)
ID : 01EK1603A-Neuro2D3
Pays : International
Organisme : European Regional Development Fund
ID : EFRE-0800977
Pays : International
Organisme : European Regional Development Fund
ID : EFRE-0800978
Pays : International
Informations de copyright
© 2019 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.
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