TY  - JOUR
AU  - Weykopf, Beatrice
AU  - Haupt, Simone
AU  - Jungverdorben, Johannes
AU  - Flitsch, Lea Jessica
AU  - Hebisch, Matthias
AU  - Liu, Guang-Hui
AU  - Suzuki, Keiichiro
AU  - Belmonte, Juan Carlos Izpisua
AU  - Peitz, Michael
AU  - Blaess, Sandra
AU  - Till, Andreas
AU  - Brüstle, Oliver
TI  - Induced pluripotent stem cell-based modeling of mutant LRRK2-associated Parkinson's disease.
JO  - European journal of neuroscience
VL  - 49
IS  - 4
SN  - 0953-816X
CY  - Oxford [u.a.]
PB  - Blackwell
M1  - DZNE-2020-06839
SP  - 561-589
PY  - 2019
AB  - 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.
KW  - Humans
KW  - Induced Pluripotent Stem Cells
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
KW  - Mitophagy
KW  - Models, Neurological
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: therapy
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7114274
C6  - pmid:30656775
DO  - DOI:10.1111/ejn.14345
UR  - https://pub.dzne.de/record/140517
ER  -