Autor(es):
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.
Data: 2019
Identificador Persistente: https://hdl.handle.net/10316/107391
Origem: Estudo Geral - Universidade de Coimbra
Assunto(s): LRRK2; Parkinson's disease; autophagy; mitochondria; mitophagy; neurodevelopment; stem cells; Aged, 80 and over; Cell Differentiation; Dopaminergic Neurons; Female; Humans; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Male; Middle Aged; Mitochondria; Neural Stem Cells; Parkinson Disease; Mutation
Descrição
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.
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.
