Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality

• Published in: Stem cell reports Vol. 12; no. 5; pp. 878 - 889
• Main Authors: Walter, Jonas, Bolognin, Silvia, Antony, Paul M.A., Nickels, Sarah L., Poovathingal, Suresh K., Salamanca, Luis, Magni, Stefano, Perfeito, Rita, Hoel, Fredrik, Qing, Xiaobing, Jarazo, Javier, Arias-Fuenzalida, Jonathan, Ignac, Tomasz, Monzel, Anna S., Gonzalez-Cano, Laura, Pereira de Almeida, Luis, Skupin, Alexander, Tronstad, Karl J., Schwamborn, Jens C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.05.2019; Elsevier
• Subjects: Aged, 80 and over; autophagy; Cell Differentiation - genetics; Dopaminergic Neurons - metabolism; Female; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - genetics; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 - metabolism; LRRK2; Male; Middle Aged; mitochondria; Mitochondria - genetics; Mitochondria - metabolism; mitophagy; Mutation; Neural Stem Cells - metabolism; neurodevelopment; Parkinson Disease - genetics; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; stem cells; stem cells; mitophagy; Parkinson's disease; autophagy; neurodevelopment; LRRK2; mitochondria
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2019.03.004

Emerging evidence suggests that Parkinson's disease (PD), besides being an age-associated disorder, might also have a neurodevelopment component. Disruption of mitochondrial homeostasis has been highlighted as a crucial cofactor in its etiology. Here, we show that PD patient-specific human neuroepithelial stem cells (NESCs), carrying the LRRK2-G2019S mutation, recapitulate key mitochondrial defects previously described only in differentiated dopaminergic neurons. By combining high-content imaging approaches, 3D image analysis, and functional mitochondrial readouts we show that LRRK2-G2019S mutation causes aberrations in mitochondrial morphology and functionality compared with isogenic controls. LRRK2-G2019S NESCs display an increased number of mitochondria compared with isogenic control lines. However, these mitochondria are more fragmented and exhibit decreased membrane potential. Functional alterations in LRRK2-G2019S cultures are also accompanied by a reduced mitophagic clearance via lysosomes. These findings support the hypothesis that preceding mitochondrial developmental defects contribute to the manifestation of the PD pathology later in life. •Mitochondrial gene expression is altered in NESCs carrying the LRRK2-G2019 mutation•LRRK2-G2019S mutation induces alterations in mitochondrial morphology in NESCs•Mitophagy is affected in PD-specific NESCs carrying the LRRK2-G2019S mutation•Mitochondrial phenotypes in NESC are rescued by genetic correction of LRRK2-G2019S Walter, Bolognin and colleagues show the detection of mitochondrial phenotypes in NESCs derived from Parkinson's disease (PD) patients carrying the LRRK2-G2019S mutation. This supports the use of stem cells as a relevant model to study PD-associated mitochondrial defects associated to PD.