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3D Cultures of Parkinson's Disease-Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing.


ABSTRACT: Parkinson's disease (PD)-specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient-specific neurons, derived from induced pluripotent stem cells carrying the LRRK2-G2019S mutation, is optimized in 3D microfluidics. The automated image analysis algorithms are implemented to enable pharmacophenomics in disease-relevant conditions. In contrast to 2D cultures, this 3D approach reveals robust endophenotypes. High-content imaging data show decreased dopaminergic differentiation and branching complexity, altered mitochondrial morphology, and increased cell death in LRRK2-G2019S neurons compared to isogenic lines without using stressor agents. Treatment with the LRRK2 inhibitor 2 (Inh2) rescues LRRK2-G2019S-dependent dopaminergic phenotypes. Strikingly, a holistic analysis of all studied features shows that the genetic background of the PD patients, and not the LRRK2-G2019S mutation, constitutes the strongest contribution to the phenotypes. These data support the use of advanced in vitro models for future patient stratification and personalized drug development.

SUBMITTER: Bolognin S 

PROVIDER: S-EPMC6325628 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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3D Cultures of Parkinson's Disease-Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing.

Bolognin Silvia S   Fossépré Marie M   Qing Xiaobing X   Jarazo Javier J   Ščančar Janez J   Moreno Edinson Lucumi EL   Nickels Sarah L SL   Wasner Kobi K   Ouzren Nassima N   Walter Jonas J   Grünewald Anne A   Glaab Enrico E   Salamanca Luis L   Fleming Ronan M T RMT   Antony Paul M A PMA   Schwamborn Jens C JC  

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20181120 1


Parkinson's disease (PD)-specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient-specific neurons, derived from induced pluripotent stem cells carrying the LRRK2-G2019S mutation, is optimized in 3D microfluidics. The automated image analysis algorithms are implemented to enable pharmacophenomics in disease-relevant conditions. In contrast to 2D cultures, this 3D approach reveals robust endophenotypes. High-content imaging data sh  ...[more]

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