Abstract
PARK2 (parkin) mutations cause early-onset Parkinson's disease (PD). Parkin is an ubiquitin E3 ligase that participates in several cellular functions, including mitochondrial homeostasis. However, the specific metabolomic changes caused by parkin depletion remain unknown. Here, we used isogenic human induced pluripotent stem cells (iPSCs) with and without PARK2 knockout (KO) to investigate the effect of parkin loss of function by comparative metabolomics supplemented with ultrastructural and functional analyses. PARK2 KO neurons displayed increased tricarboxylic acid (TCA) cycle activity, perturbed mitochondrial ultrastructure, ATP depletion, and dysregulation of glycolysis and carnitine metabolism. These perturbations were combined with increased oxidative stress and a decreased anti-oxidative response. Key findings for PARK2 KO cells were confirmed using patient-specific iPSC-derived neurons. Overall, our data describe a unique metabolomic profile associated with parkin dysfunction and show that combining metabolomics with an iPSC-derived dopaminergic neuronal model of PD is a valuable approach to obtain novel insight into the disease pathogenesis.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Stem Cell Reports |
| Vol/bind | 16 |
| Udgave nummer | 6 |
| Sider (fra-til) | 1510-1526 |
| Antal sider | 17 |
| ISSN | 2213-6711 |
| DOI | |
| Status | Udgivet - 2021 |
Bibliografisk note
Funding Information:The authors thank Dorte Lyholmer, Nadine Becker-von Buch, Ulla Melchior Hansen, and Maria Pihl for excellent technical assistance, and Dr. Claire Gudex for editing the manuscript. The live imaging experiments were performed at DaMBIC, a bioimaging core facility at the University of Southern Denmark. DaMBIC was established by an equipment grant from the Danish Agency for Science, Technology and Innovation and by internal funding from the University of Southern Denmark. The research leading to these results was supported by the Innovation Fund Denmark (BrainStem; 4108-00008A), H. Lundbeck A/S, the Danish Parkinson Foundation, the Jascha Foundation, the A.P. M?ller Foundation for the Advancement of Medical Science (15-396, 14-427), and the Faculty of Health Sciences at the University of Southern Denmark. Reprogramming of the patient fibroblasts was conducted in the James Martin Stem Cell Facility, University of Oxford, and was supported by the Monument Trust Discovery Award from Parkinson's UK, The Oxford Martin School (LC0910-004), and the Innovative Medicines Initiative Joint Undertaking under grant agreement (115439), resources of which are composed of financial contribution from the European Union's Seventh Framework Program (FP7/2007e2013) and EFPIA companies' in kind contribution. We thank the High-Throughput Genomics Group at the Wellcome Trust Center for Human Genetics, Oxford (funded by Wellcome Trust grant 090532/Z/09/Z and MRC Hub grant G0900747 91070) for the generation of Illumina genotyping data.
Funding Information:
The authors thank Dorte Lyholmer, Nadine Becker-von Buch, Ulla Melchior Hansen, and Maria Pihl for excellent technical assistance, and Dr. Claire Gudex for editing the manuscript. The live imaging experiments were performed at DaMBIC, a bioimaging core facility at the University of Southern Denmark. DaMBIC was established by an equipment grant from the Danish Agency for Science, Technology and Innovation and by internal funding from the University of Southern Denmark .
Funding Information:
The research leading to these results was supported by the Innovation Fund Denmark (BrainStem; 4108-00008A ), H. Lundbeck A/S , the Danish Parkinson Foundation , the Jascha Foundation , the A.P. Møller Foundation for the Advancement of Medical Science ( 15-396 , 14-427 ), and the Faculty of Health Sciences at the University of Southern Denmark .
Funding Information:
Reprogramming of the patient fibroblasts was conducted in the James Martin Stem Cell Facility, University of Oxford, and was supported by the Monument Trust Discovery Award from Parkinson's UK , The Oxford Martin School ( LC0910-004 ), and the Innovative Medicines Initiative Joint Undertaking under grant agreement ( 115439 ), resources of which are composed of financial contribution from the European Union's Seventh Framework Program ( FP7/2007e2013 ) and EFPIA companies' in kind contribution. We thank the High-Throughput Genomics Group at the Wellcome Trust Center for Human Genetics, Oxford (funded by Wellcome Trust grant 090532/Z/09/Z and MRC Hub grant G0900747 91070 ) for the generation of Illumina genotyping data.
Publisher Copyright:
© 2021 The Authors