Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease


Autoři: Alvaro Ingles-Prieto aff001;  Nikolas Furthmann aff002;  Samuel H. Crossman aff003;  Alexandra-Madelaine Tichy aff003;  Nina Hoyer aff005;  Meike Petersen aff005;  Vanessa Zheden aff001;  Julia Biebl aff001;  Eva Reichhart aff001;  Attila Gyoergy aff001;  Daria E. Siekhaus aff001;  Peter Soba aff005;  Konstanze F. Winklhofer aff002;  Harald Janovjak aff001
Působiště autorů: Institute of Science and Technology Austria (IST Austria), Klosterneuburg, Austria aff001;  Molecular Cell Biology, Institute of Biochemistry and Pathobiochemistry, Ruhr University Bochum, Bochum, Germany aff002;  Australian Regenerative Medicine Institute (ARMI), Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton/Melbourne, Australia aff003;  European Molecular Biology Laboratory Australia (EMBL Australia), Monash University, Clayton/Melbourne, Australia aff004;  Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany aff005
Vyšlo v časopise: Optogenetic delivery of trophic signals in a genetic model of Parkinson’s disease. PLoS Genet 17(4): e1009479. doi:10.1371/journal.pgen.1009479
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pgen.1009479

Souhrn

Optogenetics has been harnessed to shed new mechanistic light on current and future therapeutic strategies. This has been to date achieved by the regulation of ion flow and electrical signals in neuronal cells and neural circuits that are known to be affected by disease. In contrast, the optogenetic delivery of trophic biochemical signals, which support cell survival and are implicated in degenerative disorders, has never been demonstrated in an animal model of disease. Here, we reengineered the human and Drosophila melanogaster REarranged during Transfection (hRET and dRET) receptors to be activated by light, creating one-component optogenetic tools termed Opto-hRET and Opto-dRET. Upon blue light stimulation, these receptors robustly induced the MAPK/ERK proliferative signaling pathway in cultured cells. In PINK1B9 flies that exhibit loss of PTEN-induced putative kinase 1 (PINK1), a kinase associated with familial Parkinson’s disease (PD), light activation of Opto-dRET suppressed mitochondrial defects, tissue degeneration and behavioral deficits. In human cells with PINK1 loss-of-function, mitochondrial fragmentation was rescued using Opto-dRET via the PI3K/NF-кB pathway. Our results demonstrate that a light-activated receptor can ameliorate disease hallmarks in a genetic model of PD. The optogenetic delivery of trophic signals is cell type-specific and reversible and thus has the potential to inspire novel strategies towards a spatio-temporal regulation of tissue repair.

Klíčová slova:

Mitochondria – Optogenetics – Drosophila melanogaster – Light – Parkinson disease – Retina – Signal processing – Transfection


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