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Title: | Neural Stem Cells of Parkinson's Disease Patients Exhibit Aberrant Mitochondrial Morphology and Functionality | 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 Almeida, Luís Pereira de Skupin, Alexander Tronstad, Karl J. Schwamborn, Jens C. |
Keywords: | LRRK2; Parkinson's disease; autophagy; mitochondria; mitophagy; neurodevelopment; stem cells | Issue Date: | 14-May-2019 | Publisher: | Elsevier | Project: | The JCS lab is supported by the Fonds National de la Recherche (FNR) (CORE, C13/BM/5791363 and Proof-of-Concept program PoC15/11180855 & PoC16/11559169). This is an EU Joint Programme - Neurodegenerative Disease Research (JPND) project (INTER/JPND/14/02; INTER/JPND/15/11092422). Further support comes from the SysMedPD project, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement no. 668738. J.W., X.Q., L.G.-C., J.J., and A.S.M. were supported by fellowships from the FNR (AFR, Aides a` la Formation-Recherche). S.M. is supported by the FNR through the PRIDE DTU CriTiCS, reference 10907093. We also thank the private donors who support our work at the LCSB. | Serial title, monograph or event: | Stem Cell Reports | Volume: | 12 | Issue: | 5 | Abstract: | 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. | URI: | https://hdl.handle.net/10316/107391 | ISSN: | 22136711 | DOI: | 10.1016/j.stemcr.2019.03.004 | Rights: | openAccess |
Appears in Collections: | FFUC- Artigos em Revistas Internacionais I&D CNC - Artigos em Revistas Internacionais |
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