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Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality
oleh: Jonas Walter, Silvia Bolognin, Paul M.A. Antony, Sarah L. Nickels, Suresh K. Poovathingal, Luis Salamanca, Stefano Magni, Rita Perfeito, Fredrik Hoel, Xiaobing Qing, Javier Jarazo, Jonathan Arias-Fuenzalida, Tomasz Ignac, Anna S. Monzel, Laura Gonzalez-Cano, Luis Pereira de Almeida, Alexander Skupin, Karl J. Tronstad, Jens C. Schwamborn
Format: | Article |
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Diterbitkan: | Elsevier 2019-05-01 |
Deskripsi
Summary: 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. : 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. Keywords: Parkinson's disease, LRRK2, neurodevelopment, stem cells, mitochondria, autophagy, mitophagy