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Induced pluripotent stem cell‐based modeling of mutant LRRK 2‐associated Parkinson's disease
Author(s) -
Weykopf Beatrice,
Haupt Simone,
Jungverdorben Johannes,
Flitsch Lea Jessica,
Hebisch Matthias,
Liu GuangHui,
Suzuki Keiichiro,
Belmonte Juan Carlos Izpisua,
Peitz Michael,
Blaess Sandra,
Till Andreas,
Brüstle Oliver
Publication year - 2019
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1111/ejn.14345
Subject(s) - lrrk2 , reprogramming , induced pluripotent stem cell , proteostasis , biology , parkinson's disease , neuroscience , microbiology and biotechnology , context (archaeology) , disease , genome editing , computational biology , bioinformatics , genetics , cell , mutation , medicine , genome , embryonic stem cell , gene , paleontology , pathology
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 ( LRRK 2), one of the most prominent monogenetic risk factors for PD linked to both familial and idiopathic forms. The LRRK 2 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 LRRK 2 and its variants in the context of PD etiopathology. These data, along with results obtained in our own studies, underscore the multifaceted role of LRRK 2 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.