PubMed:30643711 JSONTXT

{"project":"PubTator4TogoVar","denotations":[{"id":"30643711_0","span":{"begin":1051,"end":1057},"obj":"ProteinMutation"},{"id":"30643711_1","span":{"begin":881,"end":887},"obj":"ProteinMutation"},{"id":"30643711_2","span":{"begin":750,"end":756},"obj":"ProteinMutation"},{"id":"30643711_3","span":{"begin":343,"end":349},"obj":"ProteinMutation"}],"attributes":[{"id":"30643711_0_ProteinMutation","pred":"proteinmutation","subj":"30643711_0","obj":"rs34637584"},{"id":"30643711_1_ProteinMutation","pred":"proteinmutation","subj":"30643711_1","obj":"rs34637584"},{"id":"30643711_2_ProteinMutation","pred":"proteinmutation","subj":"30643711_2","obj":"rs34637584"},{"id":"30643711_3_ProteinMutation","pred":"proteinmutation","subj":"30643711_3","obj":"rs34637584"}],"text":"3D Cultures of Parkinson's Disease-Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing.\nParkinson'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."}