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@ARTICLE{Weykopf:140517,
author = {Weykopf, Beatrice and Haupt, Simone and Jungverdorben,
Johannes and Flitsch, Lea Jessica and Hebisch, Matthias and
Liu, Guang-Hui and Suzuki, Keiichiro and Belmonte, Juan
Carlos Izpisua and Peitz, Michael and Blaess, Sandra and
Till, Andreas and Brüstle, Oliver},
title = {{I}nduced pluripotent stem cell-based modeling of mutant
{LRRK}2-associated {P}arkinson's disease.},
journal = {European journal of neuroscience},
volume = {49},
number = {4},
issn = {0953-816X},
address = {Oxford [u.a.]},
publisher = {Blackwell},
reportid = {DZNE-2020-06839},
pages = {561-589},
year = {2019},
abstract = {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.},
subtyp = {Review Article},
keywords = {Humans / Induced Pluripotent Stem Cells / Leucine-Rich
Repeat Serine-Threonine Protein Kinase-2: genetics /
Mitophagy / Models, Neurological / Parkinson Disease:
genetics / Parkinson Disease: therapy},
cin = {Cell Programming Unit},
ddc = {610},
cid = {I:(DE-2719)1013013},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC7114274},
pubmed = {pmid:30656775},
doi = {10.1111/ejn.14345},
url = {https://pub.dzne.de/record/140517},
}