[en] Homozygous or compound heterozygous (biallelic) variants in PRKN are causal for PD with highly penetrant symptom expression, while the much more common heterozygous variants may predispose to PD with highly reduced penetrance, through altered mitochondrial function. In the presence of pathogenic heterozygous variants, it is therefore important to test for mitochondrial alteration in cells derived from variant carriers to establish potential presymptomatic molecular markers. We generated lymphoblasts (LCLs) and human induced pluripotent stem cell (hiPSC)-derived neurons from non-manifesting heterozygous PRKN variant carriers and tested them for mitochondrial functionality. In LCLs, we detected hyperactive mitochondrial respiration, and, although milder compared to a biallelic PRKN-PD patient, hiPSC-derived neurons of non-manifesting heterozygous variant carriers also displayed several phenotypes of altered mitochondrial function. Overall, we identified molecular phenotypes that might be used to monitor heterozygous PRKN variant carriers during the prodromal phase. Such markers might also be useful to identify individuals at greater risk of eventual disease development and for testing potential mitochondrial function-based neuroprotective therapies before neurodegeneration advances
Disciplines :
Neurology
Author, co-author :
Castelo Rueda, Maria Paulina
Zanon, Alessandra; 1Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
Gilmozzi, Valentina; 1Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
Lavdas, Alexandros; 1Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
Raftopoulou, Athina
DELCAMBRE, Sylvie ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Del Greco, Fabiola; 1Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck, Bolzano, Italy
Klein, Christine; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Pramstaller, Peter; nstitute of Neurogenetics, University of Lübeck, Lübeck, Germany
Hicks, Andrew; nstitute of Neurogenetics, University of Lübeck, Lübeck, Germany
Pichler, Irene; nstitute of Neurogenetics, University of Lübeck, Lübeck, Germany
External co-authors :
yes
Language :
English
Title :
Molecular phenotypes of mitochondrial dysfunction in clinically non-manifesting heterozygous PRKN variant carriers
Publication date :
2023
Journal title :
NPJ Parkinson's Disease
eISSN :
2373-8057
Publisher :
Nature Publishing Group, New-York, United States - New York
Peer reviewed :
Peer Reviewed verified by ORBi
Focus Area :
Systems Biomedicine
FnR Project :
FNR9631103 - Modelling Idiopathic Parkinson'S Disease-associated Somatic Variation In Dopaminergic Neurons, 2015 (01/01/2016-31/12/2022) - Anne Grünewald
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